Urinary Thioredoxin as a Biomarker of Renal Redox Dysregulation and a Companion Diagnostic to Identify Responders to Redox-Modulating Therapeutics

Abstract

Significance:

The development and progression of renal diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), are the result of heterogeneous pathophysiology that reflects a range of environmental factors and, in a lesser extent, genetic mutations. The pathophysiology specific to most kidney diseases is not currently identified; therefore, these diseases are diagnosed based on non-pathological factors. For that reason, pathophysiology-based companion diagnostics for selection of pathophysiology-targeted treatments have not been available, which impedes personalized medicine in kidney disease.

Recent Advances:

Pathophysiology-targeted therapeutic agents are now being developed for the treatment of redox dysregulation. Redox modulation therapeutics, including bardoxolone methyl, suppresses the onset and progression of AKI and CKD. On the other hand, pathophysiology-targeted diagnostics for renal redox dysregulation are also being developed. Urinary thioredoxin (TXN) is a biomarker that can be used to diagnose tubular redox dysregulation. AKI causes oxidation and urinary excretion of TXN, which depletes TXN from the tubules, resulting in tubular redox dysregulation. Urinary TXN is selectively elevated at the onset of AKI and correlates with the progression of CKD in diabetic nephropathy.

Critical Issues:

Diagnostic methods should provide information about molecular mechanisms that aid in the selection of appropriate therapies to improve the prognosis of kidney disease.

Future Directions:

A specific diagnostic method enabling detection of redox dysregulation based on pathological molecular mechanisms is much needed and could provide the first step toward personalized medicine in kidney disease. Urinary TXN is a candidate for a companion diagnostic method to identify responders to redox-modulating therapeutics. Antioxid. Redox Signal. 36, 1051–1065.

Acute Kidney Injury and Chronic Kidney Disease Are Groups of Heterogeneous Diseases

Acute kidney injury (AKI) is not a single disease with a homogeneous etiology, but a heterogeneous group of ailments distinguished based on their rate of progression and severity (22). Chronic kidney disease (CKD) also has several different etiologies and pathogeneses (46). However, these diseases are currently diagnosed from the consequences of renal failure based on serum creatinine, urine volume (128), and proteinuria (21), which are independent of pathogenesis. Despite the many advances in molecular biological studies on the pathogenesis of AKI and CKD, very few effective and specific therapies are available, other than supportive treatment (40).

The pathogenesis of AKI is largely related to oxidative stress in the kidney (6 –8). The primary reason for the kidney's susceptibility to hypoxia is the high oxygen demand and anatomical limitation to oxygen delivery to the renal tubules (33). These factors include the large metabolic demand imposed by active reabsorption of sodium (98); limitations on oxygen delivery to cortical tissue caused by the density of peritubular capillaries (165); the poor capacity for angiogenesis in the adult kidney (10); diffusive oxygen shunting between arteries and veins in the cortex and descending and ascending vasa recta in the medulla (99); the physiological requirement for low medullary blood flow to facilitate urine concentration (36); and the topography of the vascular–tubular arrangements in the outer medulla, which limits oxygen delivery to the thick ascending limb of Henle's loop (17).

In CKD, there are some common pathways that progresses to end-stage renal failure (45). The canonical pathway entails proteinuria-inducing angiotensin II (116), which increases levels of transforming growth factor (TGF)-β1 and reactive oxygen species (ROS), leading to renal tubular epithelial apoptosis, epithelial–mesenchymal transition, and fibrosis (76). Recent studies have shown that AKI can be a transition to CKD (34). The mechanisms by which AKI transitions to CKD include hypoxia (143) and microvascular rarefaction (144), mitochondrial fragmentation (77), persistent chronic inflammation and tissue senescence (61), activation of the renin–angiotensin system (81), cell cycle arrest in the G2/M phase (166), altered phenotype and function of renal-resident cells (34), and Wnt signaling (75).

Current evidence suggests that hypoxia, oxidative stress, and subsequent redox dysregulation are common pathophysiological factors in AKI, CKD, and AKI-to-CKD transition.

Renal Injury from Oxidative Stress Related to ROS Toxicity

In a healthy kidney, oxygen supply and demand are precisely matched through regulation of medullary blood flow and tubular workload (98). Medullary blood flow is regulated by the balance between vasodilation induced by prostaglandin E2 (129), nitric oxide (NO) (29), and atrial natriuretic peptide (79) and vasoconstriction induced by endothelin (115) and angiotensin II (17). Tubular workload is regulated by tubuloglomerular feedback (98). However, if medullary blood flow slows down beyond the compensatory mechanism due to various AKI triggers such as septic shock (117), invasive surgery (14), organ dysfunction such as heart failure (31), obese (86), or contrast medium (53, 156), the supply–demand balance for oxygen is disrupted, and the resultant hypoxia causes tubular damage and the development of AKI (114).

The major sources of ROS related to ischemia–reperfusion and hypoxia are mitochondrial complex I and complex III, respectively (26, 42), whereas the ROS source related to high glucose is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4, a member of the NADPH oxidase (NOX) mitochondrial NADPH oxidase family (130) (Fig. 1). Because hydrogen peroxide (H₂O₂) is a small, uncharged molecule, it easily passes through the lipid bilayers that constitute cell and organellar membranes, diffusing throughout cells and tissues in vivo (19). The hydroxyl radical (OH・) produced from H₂O₂ is a highly reactive oxidizer that readily reacts with various biomolecules, leading to oxidation of lipids (134), deoxyribonucleic acid (139), and proteins (37), which can be damaging to kidney cells (Fig. 1).

FIG. 1.

ROS cytotoxicity and a cysteine-targeted redox system. The major source of hypoxia-induced ROS is mitochondrial complex III. The major source of glucose-induced ROS is NADPH oxidase 4. The ROS include the sequential one-electron reduction products of O₂, including ・O2⁻, H₂O₂, and ・OH⁻. H₂O₂ is small and uncharged, so it easily diffuses through lipid bilayers. Hydrogen from NADPH is transported by cysteine residues in TXN-related redox-regulated proteins, and it targets cysteine residues in redox-sensitive proteins within cells to regulate their function. NADPH, nicotinamide adenine dinucleotide phosphate; ・O2⁻, superoxide anion; ・OH⁻, hydroxy radical; ROS, reactive oxygen species; TXN, thioredoxin. Color images are available online.

Excessive ROS generation is suppressed by Sirtuin (Sirt)3, the major nicotinamide adenine dinucleotide-dependent deacetylase in mitochondria, through activation of antioxidant enzymes (11, 13). Catalase, an H₂O₂ scavenger in the renal proximal tubules, inhibits interstitial fibrosis and tubular apoptosis caused by diabetes (18) and hypertension (133). Superoxide dismutase also play a role in protecting renal function (141, 167).

In addition, peroxiredoxin (PRDX) is a thioredoxin (TXN)-dependent scavenger of H₂O₂. As such, PRDX-6 transgenic mice suppress oxidative stress via p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) activation, inflammatory cell infiltration, renal damage, and mortality after lipopolysaccharide challenge (68). Infusion of exogenous PRDX-6 also suppresses renal ischemia–reperfusion injury, promotes the recovery of renal function, and increases the survival rate (41). Conversely, PRDX-5 knockout mice exhibit enhanced tubular damage and apoptosis, and reduced renal function (104), and PRDX-3 deficiency promotes fibrosis and inflammation with mitochondrial oxidative stress in obstructed and diabetic kidneys (48). Moreover, in patients with AKI, high tubular PRDX-3 expression is associated with a high probability of recovery of renal function (159).

These findings suggest that the TXN-dependent ROS scavenger PRDXs are specific therapeutics targeting ROS-mediated acute and CKDs.

Renal Injury Due to Oxidative Stress Targeting Cysteine Residues and Redox-Modulating Therapeutics

Cellular redox regulation is a specific mechanism that modulates signal transduction by targeting cysteine residues in proteins. Cysteine residues are the target of redox-modulating therapeutics (16). Cysteine residues are modified by ROS such as H₂O₂ to form disulfide bonds (105) (Fig. 1). They are also targets of hydrogen sulfide (H₂S), which is recently discovered to be synthesized in the body and acts as a signaling molecule (84, 164). H₂S production is decreased in AKI (161), CKD (8), obesity (157), and type 2 diabetes (157). On the other hand, H₂S relieved the mouse kidney injury by ischemia reperfusion (152), cisplatin (56), or obstructive kidney injury (57).

The other key molecules involved in cysteine redox modulation are 8-nitro cyclic guanosine monophosphate (cGMP) and transcription factor NF-E2-related factor 2 (Nrf2). The ROS superoxide targets NO and carbon dioxide, producing nitroso-peroxocarboxylate (124), which reacts with guanine triphosphate to produce 8-nitro cGMP (3, 4). This 8-nitro cGMP induces S-guanosylation of cysteine residues in Kelch-like ECH-associated protein 1 (Keap1), a cytoplasmic anchor and ubiquitin ligase that activates Nrf2 (125), leading to its translocation into the nucleus to activate target genes (3, 4).

The target genes of Nrf2 include TXN, TXN reductase (TXNR), PRDXs (146), glucose-6-phosphate dehydrogenase (146), glutathione transferase (50, 55), quinone oxidoreductase (NQO1) (69), heme oxygenase (HO-1) (5), drug transport genes (52), and anti-inflammatory genes (69). Inhibition of protein disulfide isomerase, a TXN chaperone protein, reduces nuclear translocation of Nrf2, leading to mitochondrial dysfunction and renal cell apoptosis (109). Conversely, TXN, TXNR1, and the glutathione pathway are major components mediating stabilization of Nrf2 via redox regulation of cysteine residues in Keap1 (128). Thus, Nrf2 is regulated by the interaction of TXN-based enzymes with oxidants (44), and cysteine residues in Keap1 are potential therapeutic targets (121).

Nrf2 inducers targeting the cysteine residues in Keap1 include bardoxolone methyl (CDDO), sulforaphane, dimethyl fumarate (Tecfidera^®), and 3-(dimethylamino)-4-((3-isothiocyanatopropyl)(methyl)amino)cyclobut-3-ene-1,2-dione as well as N-acetylcysteine and cysteamine combined with a pro-glutathione molecule (27, 35, 80, 107, 169). CDDO ameliorates oxidative stress-induced tubular injury (92) and improves glomerular filtration rate (GFR) in patients with type 2 diabetic nephropathy (108) or autosomal dominant polycystic kidney disease (38). CDDO protects against tubular damage caused by proteinuria through inhibition of mitochondrial ROS generation, and suppression of inflammation (91). Nrf-2 activation also inhibits AKI to CKD transition (73). These suggest that redox-modulating therapeutics target cysteine residues in redox-sensitive proteins.

Renal Expression of TXN and TXN-Related Proteins

TXN gene is transcriptionally activated by constitutive binding of the Nrf2/small musculoaponeurotic fibrosarcoma (Maf) complex to the antioxidant response element in its promoter region (63). Its product, TXN protein, is a 12 kDa cysteine-modifying enzyme that acts as an intracellular redox control protein that maintains a reducing environment within cells (Fig. 2). Oxidative stress leads to cellular damage resulting from the loss of intracellular NADPH (151), H⁺ donor of TXN. In catalyzing the reduction of various redox-sensitive proteins within cells, TXN is itself oxidized. The oxidized TXN is, in turn, reduced by TXNRs, making it available for reuse as a reducing agent (137).

FIG. 2.

Schema of oxidative stress-induced urinary TXN excretion and redox dysregulation within renal tubules. TXN is a redox-regulated enzyme that maintains a reducing state within cells. TXN contains multiple cysteines and regulates the function of substrate proteins in a redox-dependent manner through the redox of cysteine residues. Under normal conditions, oxidized TXN is reduced by NADPH and TXNR and then reused, but excessive oxidative stress beyond the reducing capacity of TXNR causes accumulation and extracellular secretion of oxidized TXN. TXN secreted from renal tubules is detected in the urine and is a useful biomarker indicative of redox failure. TXNR, TXN reductase. Color images are available online.

The reduction of TXN by TXNR plays an important role in the pathophysiology of AKI, since the inhibitor of TXNR, ifosfamide caused AKI dose dependently (170). TXN scavenges oxygen radicals via TXN-dependent PRDXs. TXN is also required for intrinsic production of H₂S (82). The first study examining the role of TXN in kidney disease was published in 1996 by Minakawa et al. (83), who reported that TXN expression is upregulated during rejection of transplanted kidneys. The next year, it was reported that intraperitoneal administration of ferric nitrilotriacetate, an oxidative stress inducer, elicited a 2.5-fold increase in TXN expression within the proximal tubules of mice, and that tubules strongly expressing TXN were less damaged by the oxidative stress (145).

Within kidneys, TXN and TXNR1 are present in the cytoplasm of all cell types, whereas TXNR2 is detected mainly in mitochondria. The TXN-dependent radical scavengers PRDXs -3 and -5 are also located within mitochondria, whereas PRDX-6 is found in lysosomes (96). The organs exhibiting the highest expression of TXNR messenger ribonucleic acid (mRNA) are the liver and kidney in proximal tubules of medullary rays (119). TXN mRNA and protein are localized specifically in the proximal and distal tubules. TXN-interacting protein (TXNIP) is most abundant in the glomerulus, distal tubules, and collecting ducts, and levels are significantly elevated in kidneys exhibiting diabetic nephropathy. Transgenic mice overexpressing TXN show resistance to AKI caused by ischemia/reperfusion injury (58).

Extracellular TXN Excretion by Oxidative Stress, Including AKI

TXN is secreted from several cell types through a leaderless pathway in response to various stimuli (32,118). For example, antigen-presenting dendritic cells release TXN, which is then able to enter T cells and provide the reducing environment necessary for their activation (32). Release of TXN is oxidative stress-dependent and is induced via its redox active center (67). Levels of TXN extracellular circulating plasma in the blood are known to be elevated in oxidative stress-related diseases, such as myocardial infarction (101).

In the kidney, extracellular TXN release increases in the urine with oxidative stress in AKI (59) (Fig. 2). Urinary TXN increases as early as urinary neutrophil gelatinase-associated lipocalin (NGAL) from 1 to 2 h after the initiation of cardiopulmonary bypass (59). Urinary TXN is unaffected by extrarenal oxidative stress-related diseases, such as hypoxemia or myocardial infarction (168). Moreover, urinary TXN is increased about 100-fold in response to a decrease in TXN in the renal parenchyma in AKI. In patients with AKI, the urinary TXN fraction in an oxidized state is higher than in healthy subjects. This suggests that urinary TXN is a potentially useful redox dysregulation-specific biomarker of AKI that could contribute to the establishment of oxidative stress specific AKI treatment strategies (59) (Fig. 3).

FIG. 3.

Urinary TXN as a companion diagnostic biomarker for renal redox dysregulation. Excessive oxidative stress causes TXN to be excreted from the renal tubules into the urine, resulting in a decrease in TXN levels within the renal tubules. This, in turn, leads to disruption of intracellular redox regulation and activation of redox-sensitive, cytotoxicity-related proteins such as ASK1 and TXNIP, which are both anchored and suppressed by TXN. Redox-modulating therapeutics inhibit these redox-disrupting pathways and act in a nephroprotective manner. In addition, TXN excreted in urine can be used as a biomarker to detect tubular redox disruption caused by oxidative stress. ASK1, apoptosis signal-regulated kinase 1; TXNIP, TXN-interacting protein. Color images are available online.

Urinary TXN and Pathology-Specific Diagnosis

The poor prognosis of AKI may be attributable to its delayed diagnosis, its complex etiology, and the heterogeneity of its pathogenesis (90). Attempts are being made to achieve earlier diagnoses by using novel biomarkers. These include NGAL (85, 89), kidney injury molecule-1 (KIM-1) (49), L-type fatty acid binding protein (110), and interleukin (IL)-18 (103), among others. To further improve prognosis, AKI biomarkers should provide valuable insight into the molecular mechanisms underlying this complex and heterogeneous disease and information for selecting appropriate clinical interventions (6). However, there is no diagnostic test that measures the redox state in vivo (122).

Urinary TXN is a potential biomarker that is able to capture the oxidative stress-induced redox dysregulation in AKI and CKD. TXN is secreted from tubular epithelial cells into the urine in response to oxidative stress, which depletes intratubular TXN. Urinary TXN is superior to conventional AKI biomarkers because of its direct relationship to redox dysregulation by oxidative stress. Urinary TXN makes it possible to distinguish patients who have developed redox disorders from among a heterogeneous population and to then treat them with redox-modulating therapeutics, which is expected to improve the prognosis of renal diseases (Fig. 3).

Apoptosis Signal Regulating Kinase1 as a Therapeutic Target in Kidney Disease

Apoptosis signal-regulated kinase 1 (ASK1) is a member of the mitogen-activated protein (MAP) kinase kinase family, which induces apoptosis by activating the JNK/p38 MAP kinase pathway. In the steady state, ASK1 is directly inhibited by TXN; however, oxidative stress induces S-nitrosylation of TXN and activation of ASK1 (138). ASK1+/+ mice have more severe renal dysfunction in AKI via JNK p38K and monocyte chemoattractant protein-1 (MCP-1) (147). ASK1 is also involved in the activation of Toll-like receptor 4 (TLR4), which is responsible for innate immune signaling in renal ischemia–reperfusion injury (12, 87) and in renal fibrosis in the mouse unilateral ureteral obstruction (UUO) model (74). In humans, activation of ASK1 is observed when renal allograft tubular cells experience rejection (7).

Based on those findings, ASK1 inhibition is thought to be a potentially useful therapeutic target for treatment of fibrosis in both AKI and CKD (148). Selonsertib (GS-4997) and GS-444217, orally administered ASK1 inhibitors, are effective for the treatment of diabetic kidney disease (25, 71) and liver fibrosis (100, 171).

TXN and TXNIP in Kidney Diseases

CKD is defined as proteinuria or abnormal renal function lasting more than 3 months. CKD can be caused by a variety of disorders, including diabetes, hypertension, chronic glomerulonephritis, and AKI. The onset and progression of CKD are mediated via multiple mechanisms, including the TXN redox system. Systemic overexpression of TXN in mice prevents the onset of diabetic nephropathy (43). Urinary excretion of TXN correlates positively with the rate of annual estimated GFR (eGFR) decline in patients with diabetic nephropathy (150). H₂S converts oxidized TXN to reduced TXN and promotes dissociation of TXN from TXNIP; it inhibits cell injury (78).

TXNIP, also known as vitamin D3 upregulated protein 1 (VDUP1) or TXN binding protein-2 (TBP-2), was first identified in 1999 by Nishiyama et al. (95) as a negative regulator of TXN (54). Nrf2 represses TXNIP expression by binding to the antioxidant response element (−1286 to −1276) of the TXNIP promoter, which prevents the induction of TXNIP by high glucose (44). TXNIP plays a key role in the induction of NOX4 via an ROS signaling pathway under conditions of hyperglycemic stress (131). High glucose increases TXNIP transactivation via a TGF-β1-independent pathway (111), but it is mediated by the transcription factors Krüppel-like factor 6 (KLF6) and peroxisome proliferator-activated receptor γ (112) as well as epigenetic mechanisms (30) and several microRNAs (153).

High glucose increases TXNIP expression and decreases TXN expression, and TXNIP knockdown inhibits the progression of diabetic nephropathy (2, 132). TXNIP knockout suppresses hyperglycemia-induced tubular transformation (155). The allergy medication tranilast suppresses TXNIP and oxidative stress in an animal model of diabetic nephropathy (142). Elevated levels of TXNIP in urinary sediment from patients with type 1 diabetes are associated with decreased eGFR and diabetic kidney disease (88). TXNIP also regulates collagen expression in mesangial cells in patients with CKD (131). Advanced glycation end products also increase TXNIP (149).

TXNIP Targets Inflammasome in CKD

The specific mechanism by which TXNIP contributes to the pathophysiology of diabetic nephropathy and CKD was clarified in a recent study (172). TXNIP binds to the nod-like receptor protein 3 (NLRP3) inflammasome complex (172), resulting in increased proteinuria and albuminuria as well as podocytosis and glomerulopathy (1). These effects can be ameliorated via the mammalian target of rapamycin inhibition achieved through TXNIP suppression (132, 136, 137).

Inflammasomes are the center of an innate immune pathway in which sterile inflammation occurs in a pathogen-free environment. TXNIP is involved in the NLRP3 inflammasome. Pattern recognition receptors such as NLRP3, absent in melanoma 2 (AIM2) and NLR family CARD domain containing protein 4 (NLRC4), undergo structural changes on recognition of specific stimuli (agonists) and associate with proteins such as apoptosis-associated speck like protein (ASC) and caspase-1 to form a complex called an inflammasome. In other words, the TXN-TXNIP system serves as a conduit between oxidative stress and innate immunity. Abais et al. used molecular-weight exclusion chromatography and confocal microscopy to observe cultured podocytes with and without verapamil-induced TXNIP inhibition. Their results showed that stimulation with high homocysteine mobilizes TXNIP into the NLRP3 inflammasome complex, which is then involved in increasing caspase-1 activity and IL-1β production (1). TXNIP also plays a role in the induction of tubular autophagy (47).

Activation of TXNIP and NLRP3 is associated with renal ischemia/reperfusion-mediated induction of AKI via production of cleaved caspase-1, IL-1 β, and IL-18 (163). Inhibition of TXNIP suppresses production of type IV collagen and interstitial fibrosis in rats with streptozotocin-induced diabetic nephropathy (140). Moreover, TXNIP knockout in UUO model mice suppresses the renal fibrosis; macrophage invasion; apoptosis; α-smooth muscle actin (α-SMA), TGF-β1, connective tissue growth factor (CTGF) and MCP-1 expression; NLRP3 inflammasome formation; and Smad3, p38 MAPK, ERK1/2, nuclear factor-kappa B (NF-κB), 8-hydroxy-2'-deoxyguanosine (8-OHdG), hemoxigenase-1, and Nox4 activation seen in wild-type mice (160). These findings suggest that the preventive effect on diabetic nephropathy of targeting TXNIP may be mediated via an NLRP3 inflammasome-autophagy pathway.

AKI and Multiple Organ Failure

Systemic infections, including severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]), are associated with AKI and cause multiorgan dysfunction (23, 106, 117). The flavonoid quercetin suppresses the NLRP3 inflammasome via regulators such as TXNIP, SIRT1, and Nrf2 and it is a potential treatment for severe inflammation in patients with COVID-19 (120). It has become clear that kidney failure leads to failure of multiple organs (126). The high mortality rates in AKI (24, 70) are thought to be the result of multiple distant organ failure, not the kidney dysfunction per se (126). AKI leads to insufficient clearance of soluble IL-6, which has been shown to increase vascular permeability and cell inflammation via dysregulation of salt and water channels in the lung (113), brain (72), heart (60), liver, bone marrow, and gastrointestinal tract.

Notably, TXN is reportedly effective against this AKI-multiorgan system linkage. For example, a long half-life human albumin-TXN fusion protein (HSA-TXN) reduces lung injury caused by bilateral renal ischemia/reperfusion injury, suppresses increases in plasma IL-6 levels, and reduces macrophage migration inhibitory factor (MIF) expression and IL-6-CXC chemokine ligand (CXCL)1/2-mediated neutrophil infiltration into the lung (93). In addition, HSA-TXN significantly increases the survival rate among mice subjected to renal ischemia/reperfusion injury (93). Inhibitors of ASK1 are potential drug targets to suppress multiorgan dysfunction (100). These findings suggest that redox-modulating therapeutics may be useful for treatment of the multiorgan-renal syndrome caused by AKI. The heterogeneity of the AKI patient population can be solved by diagnosing AKI from the viewpoint of redox dysregulation (Fig. 4).

FIG. 4.

Combining companion diagnostics for redox disruption and treatment with redox-targeted therapeutics may improve the prognosis of oxidative stress-dominant multiple organ failure. AKI often leads to multiorgan failure due to insufficient clearance of soluble cytokines and hormonal dysfunction. AKI can be caused by a variety of factors, including oxidative stress. The usefulness of several redox-modulating therapeutics against oxidative stress-induced redox disruption has been proposed and is about to be commercialized. At present, redox-modulating therapeutics are being tested in a heterogeneous population diagnosed based on only renal function and urine output, but it is expected that they will be more effective when selectively administered to patients with redox disruption. Measurement of urinary TXN may be a useful means of identifying patients with redox disruption. The combination of redox-modulating therapeutics and diagnosis of redox disruption using urinary TXN is expected to improve the prognosis of AKI and its associated multiorgan failure. AKI, acute kidney injury. Color images are available online.

TXN and Macrophage MIF in Kidney Diseases

HSA-TXN suppresses AKI induced by contrast medium (65), cisplatin (64), or rhabdomyolysis (94). HSA-TXN inhibits the production of 8-nitro-cGMP (39) and suppresses renal ischemia/reperfusion injury-induced expression of MIF (94, 95). Intracellularly, MIF directly binds to and interacts with TXN (135) and TXNIP (62), and has been implicated in various diseases ranging from inflammatory diseases such as sepsis, rhinitis, and rheumatoid arthritis, to heart failure, myocardial infarction, AKI, organ fibrosis, and numerous malignancies (51). The MIF transgenic mice exhibit progressive increases in matrix within the mesangium with collagen IV accumulation. Mice showing a high expression of MIF often died of renal failure at 8 weeks, but most survived, despite significant proteinuria and progressive renal failure. Podocytes from these transgenic mice frequently exhibited characteristic ultrastructural changes, including cell flattening, contracted foot processes, and chorionic transformation (123). The MIF is also reported to be a cystic growth factor in autosomal dominant polycystic kidney disease (20).

TXN and Personalized Medicine in Kidney Disease

Personalized medicine aims at providing the right drug to the right patient at the right time (28). Personalized medicine also has advantages for drug development (158). Oncology is at the forefront of personalized medicine (102) because the specific genetic mutation is, itself, the pathophysiology that is the target of the therapeutic agents and companion diagnostics (9). On the other hand, many difficulties remain before personalized medicine in kidney diseases (28). Our current understanding of the interactions between the genetic and environmental factors that determine the appropriate targeted therapies for treatment is incomplete (97) (Fig. 5). For example, the latest high-throughput sequencing technologies revealed hundreds of gene mutations and genetic variants associated with renal disease (162). However, important gaps remain in our understanding of the mechanisms of action of the genetic components of CKD (97). In addition, CKD is often not due to expected environmental causes such as diabetes or hypertension, and no other conditions have exhibited a cause–effect relationship with CKD (154).

FIG. 5.

Unresolved causal factors and the difficulties in achieving personalized medicine in kidney disease. Personalized medicine based on pharmacogenetics has proved highly useful in oncology, because genetic factors play a major role in its pathophysiology. On the other hand, kidney diseases develop and progress due to both genetic and environmental factors, none of which has been identified as clearly related to the disease. Therefore, an alternative target that substitutes genetic or environmental factors is required to realize personalized medicine that combines companion diagnostics with targeted therapeutics. The common pathophysiology of AKI and CKD could be the alternative target for personalized medicine. The key to realizing personalized medicine for kidney disease is to develop combinations of diagnostics and therapeutics that target its pathophysiology. CKD, chronic kidney disease. Color images are available online.

At present, therefore, the pharmacogenomics are not a suitable basis for personalized medicine in kidney diseases. As the second-best alternative, pathophysiological causes that are neither genetic nor environmental should be targeted for companion diagnostics (15). The evidence summarized in this article suggests that redox dysregulation resulting from oxidative stress, hypoxia, or ROS is a common etiology in AKI and CKD and would be an effective new target for diagnosis and treatment of these kidney diseases. Renal redox dysregulation increases urinary TXN (59), which could serve as a useful companion diagnostic biomarker to identify responders to redox-modulating therapeutics (Fig. 6). For right-time diagnoses, rapid measuring equipment has been developed for urinary TXN (168). Chemiluminescent enzyme immunoassays for TXN can be completed in <6 min, as compared with the more than 4 h required to complete conventional enzyme-linked immunosorbent assays (66). Urinary TXN could give physicians the ability to provide redox-modulating therapeutics to the right patients at the right time, enabling the first step toward personalized medicine in kidney disease.

FIG. 6.

Improving the response rate to redox-modulating therapeutics through personalized medicine using urinary TXN. AKI, AKD, and CKD are all complicated, heterogenic diseases. Because of their heterogeneity, it is expected that there will be a mixture of responders and non-responders to treatments. Subtyping patients using pathology-specific biomarkers would improve the efficacy of pathology-specific therapies by sorting out groups with homogeneous pathologies and excluding non-responders. Urinary TXN, which is specific for redox dysregulation, is useful for pathospecific subtyping of AKI. The indicated biomarkers are pathophysiology-specific. The indicated pathospecific treatments are the pathophysiology-based therapeutics associated with the respective biomarkers used for companion diagnostics. AKD, acute kidney disease. Color images are available online.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This article is prepared with funding from the Japan Society for the Promotion of Science (JSPS KAKENHI grant nos. JP21K08252, JP20K09143, JP20H03696, JP20K08630, and JP18K08203), research grants from the Life Science Innovation Center, University of Fukui to K.K. and from the Headquarters for Innovation Society-Academia Cooperation, University of Fukui to K.K. Dr. William F. Goldman, MST Editing Company, provided writing and editorial assistance. Mr. Takashi TSUJINO, Science Graphics. Co., Ltd., provided assistance in the preparation of high-resolution images based on authors' detailed directions.

Abbreviations Used

References

Abais

, Xia

, Li

, Chen

, Conley

, Gehr

TWB

, Boini

, and Li

P-L

. Nod-like receptor protein 3 (NLRP3) inflammasome activation and podocyte injury via thioredoxin-interacting protein (TXNIP) during hyperhomocysteinemia. J Biol Chem, 289: 27159–27168, 2014.

Advani

, Gilbert

, Thai

, Gow

, Langham

, Cox

, Connelly

, Zhang

, Herzenberg

, Christensen

, Pollock

, Qi

, Tan

, Parving

H-H

, and Kelly

. Expression, localization, and function of the thioredoxin system in diabetic nephropathy. J Am Soc Nephrol JASN, 20: 730–741, 2009.

Ahmed

, Sawa

, Ihara

, Kasamatsu

, Yoshitake

, Rahaman

, Okamoto

, Fujii

, and Akaike

. Regulation by mitochondrial superoxide and NADPH oxidase of cellular formation of nitrated cyclic GMP: potential implications for ROS signalling. Biochem J, 441: 719–730, 2012.

Akaike

, Nishida

, and Fujii

. Regulation of redox signalling by an electrophilic cyclic nucleotide. J Biochem (Tokyo), 153: 131–138, 2013.

Alam

, Wicks

, Stewart

, Gong

, Touchard

, Otterbein

, Choi

, Burow

, and Tou

. Mechanism of heme oxygenase-1 gene activation by cadmium in MCF-7 mammary epithelial cells. Role of p38 kinase and Nrf2 transcription factor. J Biol Chem, 275: 27694–27702, 2000.

Alge

and Arthur

. Biomarkers of AKI: a review of mechanistic relevance and potential therapeutic implications. Clin J Am Soc Nephrol CJASN, 10: 147–155, 2015.

Al-Lamki

, Wang

, Vandenabeele

, Bradley

, Thiru

, Luo

, Min

, Pober

, and Bradley

. TNFR1- and TNFR2-mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury. FASEB J Off Publ Fed Am Soc Exp Biol, 19: 1637–1645, 2005.

Aminzadeh

and Vaziri

. Downregulation of the renal and hepatic hydrogen sulfide (H2S)-producing enzymes and capacity in chronic kidney disease. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc Eur Ren Assoc, 27: 498–504, 2012.

August

Emerging companion diagnostics for cancer drugs. Nat Rev Drug Discov, 9: 351, 2010.

10.

Basile

, Friedrich

, Spahic

, Knipe

, Mang

, Leonard

, Changizi-Ashtiyani

, Bacallao

, Molitoris

, and Sutton

. Impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction following acute kidney injury. Am J Physiol Renal Physiol, 300: F721–F733, 2011.

11.

Bell

and Guarente

. The SirT3 divining rod points to oxidative stress. Mol Cell, 42: 561–568, 2011.

12.

Ben Mkaddem

, Pedruzzi

, Werts

, Coant

, Bens

, Cluzeaud

, Goujon

, Ogier-Denis

, and Vandewalle

. Heat shock protein gp96 and NAD(P)H oxidase 4 play key roles in Toll-like receptor 4-activated apoptosis during renal ischemia/reperfusion injury. Cell Death Differ, 17: 1474–1485, 2010.

13.

Benigni

, Corna

, Zoja

, Sonzogni

, Latini

, Salio

, Conti

, Rottoli

, Longaretti

, Cassis

, Morigi

, Coffman

, and Remuzzi

. Disruption of the Ang II type 1 receptor promotes longevity in mice. J Clin Invest, 119: 524–530, 2009.

14.

Billings

, Pretorius

, Schildcrout

, Mercaldo

, Byrne

, Ikizler

, and Brown

. Obesity and oxidative stress predict AKI after cardiac surgery. J Am Soc Nephrol, 23: 1221–1228, 2012.

15.

Bochud

, Burnier

, and Guessous

. Top three pharmacogenomics and personalized medicine applications at the nexus of renal pathophysiology and cardiovascular medicine. Curr Pharmacogenomics Pers Med, 9: 299–322, 2011.

16.

Bourgonje

, Feelisch

, Faber

, Pasch

, Dijkstra

, and Goor

H van

. Oxidative stress and redox-modulating therapeutics in inflammatory bowel disease. Trends Mol Med, 26: 1034–1046, 2020.

17.

Brezis

and Rosen

. Hypoxia of the renal medulla—its implications for disease. N Engl J Med, 332: 647–655, 1995.

18.

Brezniceanu

M-L

, Liu

, Wei

C-C

, Chénier

, Godin

, Zhang

S-L

, Filep

, Ingelfinger

, and Chan

JSD

. Attenuation of interstitial fibrosis and tubular apoptosis in db/db transgenic mice overexpressing catalase in renal proximal tubular cells. Diabetes, 57: 451–459, 2008.

19.

Brieger

, Schiavone

, Miller

, and Krause

K-H

. Reactive oxygen species: from health to disease. Swiss Med Wkly, 142: w13659, 2012.

20.

Chen

, Zhou

, Fan

, Yao

, Swenson-Fields

, Gadjeva

, Wallace

, Peters

DJM

, Yu

, Grantham

, and Li

. Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease. J Clin Invest, 125: 2399–2412, 2015.

21.

Chen

, Knicely

, and Grams

. Chronic kidney disease diagnosis and management: a review. JAMA, 322: 1294–1304, 2019.

22.

Chen

Current definition of acute kidney injury actually identifies a heterogenous group of patients with elevated serum creatinine and reduced urine output. Crit Care Lond Engl, 24: 247, 2020.

23.

Cheng

, Luo

, Wang

, Zhang

, Wang

, Dong

, Li

, Yao

, Ge

, and Xu

. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int, 97: 829–838, 2020.

24.

Chertow

, Burdick

, Honour

, Bonventre

, and Bates

. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol JASN, 16: 3365–3370, 2005.

25.

Chertow

, Pergola

, Chen

, Kirby

, Sundy

, Patel

, and GS-US-223-1015 Investigators . Effects of selonsertib in patients with diabetic kidney disease. J Am Soc Nephrol JASN, 30: 1980–1990, 2019.

26.

Chouchani

, Pell

, James

, Work

, Saeb-Parsy

, Frezza

, Krieg

, and Murphy

. A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury. Cell Metab, 23: 254–263, 2016.

27.

Crinelli

, Zara

, Galluzzi

, Buffi

, Ceccarini

, Smietana

, Mari

, Magnani

, and Fraternale

. Activation of NRF2 and ATF4 signaling by the pro-glutathione molecule I-152, a co-drug of N-acetyl-cysteine and cysteamine. Antioxid Basel Switz, 10: 175, 2021.

28.

Curran

and Platero

. Diagnostics and personalized medicine: observations from the World Companion Diagnostics Summit. Pharmacogenomics, 12: 465–470, 2011.

29.

Dautzenberg

and Just

. Temporal characteristics of nitric oxide-, prostaglandin-, and EDHF-mediated components of endothelium-dependent vasodilation in the kidney. Am J Physiol Regul Integr Comp Physiol, 305: R987–R998, 2013.

30.

De Marinis

, Cai

, Bompada

, Atac

, Kotova

, Johansson

, Garcia-Vaz

, Gomez

, Laakso

, and Groop

. Epigenetic regulation of the thioredoxin-interacting protein (TXNIP) gene by hyperglycemia in kidney. Kidney Int, 89: 342–353, 2016.

31.

Doi

Kidney-heart interactions in acute kidney injury. Nephron, 134: 141–144, 2016.

32.

Ericson

, Hörling

, Wendel-Hansen

, Holmgren

, and Rosén

. Secretion of thioredoxin after in vitro activation of human B cells. Lymphokine Cytokine Res, 11: 201–207, 1992.

33.

Evans

, Smith

, Lee

C-J

, Ngo

, and Gardiner

. What makes the kidney susceptible to hypoxia?. Anat Rec Hoboken NJ 2007, 303: 2544–2552, 2020.

34.

Fiorentino

, Grandaliano

, Gesualdo

, and Castellano

. Acute kidney injury to chronic kidney disease transition. Contrib Nephrol, 193: 45–54, 2018.

35.

Fourquet

, Guerois

, Biard

, and Toledano

. Activation of NRF2 by nitrosative agents and H2O2 involves KEAP1 disulfide formation. J Biol Chem, 285: 8463–8471, 2010.

36.

Fry

, Edwards

, and Layton

. Impacts of nitric oxide and superoxide on renal medullary oxygen transport and urine concentration. Am J Physiol Renal Physiol, 308: F967–F980, 2015.

37.

Fujii

, Sawa

, Ihara

, Tong

, Ida

, Okamoto

, Ahtesham

, Ishima

, Motohashi

, Yamamoto

, and Akaike

. The critical role of nitric oxide signaling, via protein S-guanylation and nitrated cyclic GMP, in the antioxidant adaptive response. J Biol Chem, 285: 23970–23984, 2010.

38.

Fujiki

, Ando

, Murakami

, Isobe

, Mori

, Susa

, Nomura

, Sohara

, Rai

, and Uchida

. Tolvaptan activates the Nrf2/HO-1 antioxidant pathway through PERK phosphorylation. Sci Rep, 9: 9245, 2019.

39.

Furukawa

, Tanaka

, Chuang

VTG

, Ishima

, Taguchi

, Watanabe

, Maruyama

, and Otagiri

. Human serum albumin-thioredoxin fusion protein with long blood retention property is effective in suppressing lung injury. J Control Release Off J Control Release Soc, 154: 189–195, 2011.

40.

Gao

, Zhong

, Jin

, Li

, and Meng

X-M

. Potential targeted therapy and diagnosis based on novel insight into growth factors, receptors, and downstream effectors in acute kidney injury and acute kidney injury-chronic kidney disease progression. Signal Transduct Target Ther, 5: 9, 2020.

41.

Goncharov

, Rogov

, Temnov

, Novoselov

, and Sharapov

. Protective role of exogenous recombinant peroxiredoxin 6 under ischemia-reperfusion injury of kidney. Cell Tissue Res, 378: 319–332, 2019.

42.

Guzy

, Hoyos

, Robin

, Chen

, Liu

, Mansfield

, Simon

, Hammerling

, and Schumacker

. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab, 1: 401–408, 2005.

43.

Hamada

, Miyata

, Nii-Kono

, Kitazawa

, Higo

, Fukunaga

, Ueyama

, Nakamura

, Yodoi

, Fukagawa

, and Kasuga

. Overexpression of thioredoxin1 in transgenic mice suppresses development of diabetic nephropathy. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc Eur Ren Assoc, 22: 1547–1557, 2007.

44.

and Ma

. Redox regulation by nuclear factor erythroid 2-related factor 2: gatekeeping for the basal and diabetes-induced expression of thioredoxin-interacting protein. Mol Pharmacol, 82: 887–897, 2012.

45.

Hostetter

, Rennke

, and Brenner

. Compensatory renal hemodynamic injury: a final common pathway of residual nephron destruction. Am J Kidney Dis Off J Natl Kidney Found, 1: 310–314, 1982.

46.

Hoyer

KJR

, Dittrich

, Bartram

, and Rinschen

. Quantification of molecular heterogeneity in kidney tissue by targeted proteomics. J Proteomics, 193: 85–92, 2019.

47.

Huang

, Lin

, Cheng

, Braet

, Pollock

, and Chen

X-M

. Thioredoxin-interacting protein mediates dysfunction of tubular autophagy in diabetic kidneys through inhibiting autophagic flux. Lab Investig J Tech Methods Pathol, 94: 309–320, 2014.

48.

Hwang

, Uddin

, Lee

, Jiang

, Pak

, and Ha

. Peroxiredoxin 3 deficiency accelerates chronic kidney injury in mice through interactions between macrophages and tubular epithelial cells. Free Radic Biol Med, 131: 162–172, 2019.

49.

Ichimura

, Bonventre

, Bailly

, Wei

, Hession

, Cate

, and Sanicola

. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem, 273: 4135–4142, 1998.

50.

Ikeda

, Serria

, Kakizaki

, Hatayama

, Satoh

, Tsuchida

, Muramatsu

, Nishi

, and Sakai

. Activation of mouse Pi-class glutathione S-transferase gene by Nrf2(NF-E2-related factor 2) and androgen. Biochem J, 364: 563–570, 2002.

51.

Jankauskas

, Wong

DWL

, Bucala

, Djudjaj

, and Boor

. Evolving complexity of MIF signaling. Cell Signal, 57: 76–88, 2019.

52.

Jeddi

, Soozangar

, Sadeghi

, Somi

, Shirmohamadi

, Eftekhar-Sadat

A-T

, and Samadi

. Nrf2 overexpression is associated with P-glycoprotein upregulation in gastric cancer. Biomed Pharmacother Biomedecine Pharmacother, 97: 286–292, 2018.

53.

Jeong

, Lee

, Park

, Kang

, Yu

S-L

, Choi

D-R

, Han

S-Y

, Park

, Cho

, Lee

, Hwang

W-M

, Yun

S-R

, Ryu

H-M

, Oh

E-J

, Park

S-H

, Kim

Y-L

, and Yoon

S-H

. Oxidative stress caused by activation of NADPH oxidase 4 promotes contrast-induced acute kidney injury. PLoS One, 13: e0191034, 2018.

54.

Junn

, Han

, Im

, Yang

, Cho

, Um

, Kim

, Lee

, Han

, Rhee

, and Choi

. Vitamin D3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function. J Immunol Baltim Md 1950, 164: 6287–6295, 2000.

55.

Kang

, Choi

, and Kim

. Peroxynitrite activates NF-E2-related factor 2/antioxidant response element through the pathway of phosphatidylinositol 3-kinase: the role of nitric oxide synthase in rat glutathione S-transferase A2 induction. Nitric Oxide Biol Chem, 7: 244–253, 2002.

56.

Karimi

, Absalan

, Khorsandi

, Valizadeh

, and Mansouri

. Sodium hydrogen sulfide (NaHS) ameliorates alterations caused by cisplatin in filtration slit diaphragm and podocyte cytoskeletal in rat kidney. J Nephropathol, 6: 150–156, 2017.

57.

Kasinath

BS.

Hydrogen sulfide to the rescue in obstructive kidney injury. Kidney Int, 85: 1255–1258, 2014.

58.

Kasuno

, Nakamura

, Ono

, Muso

, and Yodoi

. Protective roles of thioredoxin, a redox-regulating protein, in renal ischemia/reperfusion injury. Kidney Int, 64: 1273–1282, 2003.

59.

Kasuno

, Shirakawa

, Yoshida

, Mori

, Kimura

, Takahashi

, Nobukawa

, Shigemi

, Tanabe

, Yamada

, Koshiji

, Nogaki

, Kusano

, Ono

, Uno

, Nakamura

, Yodoi

, Muso

, and Iwano

. Renal redox dysregulation in AKI: application for oxidative stress marker of AKI. Am J Physiol Renal Physiol, 307: F1342–F1351, 2014.

60.

Kelly

KJ.

Distant effects of experimental renal ischemia/reperfusion injury. J Am Soc Nephrol JASN, 14: 1549–1558, 2003.

61.

Kim

M-G

, Yang

, Ko

, Lee

, Oh

, Cho

, and Jo

S-K

. Impact of aging on transition of acute kidney injury to chronic kidney disease. Sci Rep, 9: 18445, 2019.

62.

Kim

, Kim

, Byun

J-E

, Huy

, Lee

, Song

, Park

Y-J

, Kim

T-D

, Yoon

, Choi

E-J

, Ha

, Jung

, and Choi

. Macrophage migration inhibitory factor interacts with thioredoxin-interacting protein and induces NF-κB activity. Cell Signal, 34: 110–120, 2017.

63.

Kim

, Masutani

, Yamaguchi

, Itoh

, Yamamoto

, and Yodoi

. Hemin-induced activation of the thioredoxin gene by Nrf2. A differential regulation of the antioxidant responsive element by a switch of its binding factors. J Biol Chem, 276: 18399–18406, 2001.

64.

Kodama

, Watanabe

, Tanaka

, Kondo

, Chuang

VTG

, Wu

, Endo

, Ishima

, Fukagawa

, Otagiri

, and Maruyama

. Albumin fusion renders thioredoxin an effective anti-oxidative and anti-inflammatory agent for preventing cisplatin-induced nephrotoxicity. Biochim Biophys Acta, 1840: 1152–1162, 2014.

65.

Kodama

, Watanabe

, Tanaka

, Chuang

VTG

, Miyamoto

, Wu

, Endo

, Hamasaki

, Ishima

, Fukagawa

, Otagiri

, and Maruyama

. A human serum albumin-thioredoxin fusion protein prevents experimental contrast-induced nephropathy. Kidney Int, 83: 446–454, 2013.

66.

Kogaki

, Fujiwara

, Yoshiki

, Kitajima

, Tanimoto

, Mitsui

, Shimamura

, Hamuro

, and Ashihara

. Sensitive enzyme-linked immunosorbent assay for adult T-cell leukemia-derived factor and normal value measurement. J Clin Lab Anal, 10: 257–261, 1996.

67.

Kondo

, Ishii

, Kwon

Y-W

, Tanito

, Horita

, Nishinaka

, Nakamura

, and Yodoi

. Redox-sensing release of human thioredoxin from T lymphocytes with negative feedback loops. J Immunol, 172: 442–448, 2004.

68.

Lee

, Park

, Han

, Yoon

, Jung

, and Hong

. Peroxiredoxin 6 overexpression attenuates lipopolysaccharide-induced acute kidney injury. Oncotarget, 8: 51096–51107, 2017.

69.

Lee

J-M

, Calkins

, Chan

, Kan

, and Johnson

. Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J Biol Chem, 278: 12029–12038, 2003.

70.

Levy

, Viscoli

, and Horwitz

. The effect of acute renal failure on mortality. A cohort analysis. JAMA, 275: 1489–1494, 1996.

71.

Liles

, Corkey

, Notte

, Budas

, Lansdon

, Hinojosa-Kirschenbaum

, Badal

, Lee

, Schultz

, Wise

, Pendem

, Graupe

, Castonguay

, Koch

, Wong

, Papalia

, French

, Sullivan

, Huntzicker

, Ma

, Nikolic-Paterson

, Altuhaifi

, Yang

, Fogo

, and Breckenridge

. ASK1 contributes to fibrosis and dysfunction in models of kidney disease. J Clin Invest, 128: 4485–4500, 2018.

72.

Liu

, Liang

, Chigurupati

, Lathia

, Pletnikov

, Sun

, Crow

, Ross

, Mattson

, and Rabb

. Acute kidney injury leads to inflammation and functional changes in the brain. J Am Soc Nephrol JASN, 19: 1360–1370, 2008.

73.

, Wang

, Qiao

, Jiang

, Ge

, Flickinger

, Malhotra

, Dworkin

, Liu

, and Gong

. GSK3β-mediated Keap1-independent regulation of Nrf2 antioxidant response: a molecular rheostat of acute kidney injury to chronic kidney disease transition. Redox Biol, 26: 101275, 2019.

74.

, Tesch

, and Nikolic-Paterson

. ASK1/p38 signaling in renal tubular epithelial cells promotes renal fibrosis in the mouse obstructed kidney. Am J Physiol Renal Physiol, 307: F1263–F1273, 2014.

75.

Maarouf

, Aravamudhan

, Rangarajan

, Kusaba

, Zhang

, Welborn

, Gauvin

, Hou

, Kramann

, and Humphreys

. Paracrine Wnt1 drives interstitial fibrosis without inflammation by tubulointerstitial cross-talk. J Am Soc Nephrol JASN, 27: 781–790, 2016.

76.

Macconi

, Remuzzi

, and Benigni

. Key fibrogenic mediators: old players. Renin-angiotensin system. Kidney Int Suppl, 4: 58–64, 2014.

77.

Maekawa

and Inagi

. Pathophysiological role of organelle stress/crosstalk in AKI-to-CKD transition. Semin Nephrol, 39: 581–588, 2019.

78.

Mao

, Huang

, Zhang

, Yang

, Zhang

, Huang

, Sawada

, Mitsui

, Takeda

, and Yao

. Pharmacological levels of hydrogen sulfide inhibit oxidative cell injury through regulating the redox state of thioredoxin. Free Radic Biol Med, 134: 190–199, 2019.

79.

Marin-Grez

, Fleming

, and Steinhausen

. Atrial natriuretic peptide causes pre-glomerular vasodilatation and post-glomerular vasoconstriction in rat kidney. Nature, 324: 473–476, 1986.

80.

Masutani

, Otsuki

, Yamaguchi

, Takenaka

, Kanoh

, Takatera

, Kunimoto

, and Yodoi

. Fragrant unsaturated aldehydes elicit activation of the Keap1/Nrf2 system leading to the upregulation of thioredoxin expression and protection against oxidative stress. Antioxid Redox Signal, 11: 949–962, 2009.

81.

Mehrotra

, Patel

, Ivancic

, Collett

, and Basile

. Th-17 cell activation in response to high salt following acute kidney injury is associated with progressive fibrosis and attenuated by AT-1R antagonism. Kidney Int, 88: 776–784, 2015.

82.

Mikami

, Shibuya

, Kimura

, Nagahara

, Ogasawara

, and Kimura

. Thioredoxin and dihydrolipoic acid are required for 3-mercaptopyruvate sulfurtransferase to produce hydrogen sulfide. Biochem J, 439: 479–485, 2011.

83.

Minakawa

, Nakamura

, Holmgren

, Yodoi

, Lindholm

, Tydén

, and Reinholt

. Expression of ATL-derived factor/human thioredoxin in rejected kidney grafts. Transplant Proc, 28: 1463–1464, 1996.

84.

Mishanina

, Libiad

, and Banerjee

. Biogenesis of reactive sulfur species for signaling by hydrogen sulfide oxidation pathways. Nat Chem Biol, 11: 457–464, 2015.

85.

Mishra

, Dent

, Tarabishi

, Mitsnefes

, Ma

, Kelly

, Ruff

, Zahedi

, Shao

, Bean

, Mori

, Barasch

, and Devarajan

. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet Lond Engl, 365: 1231–1238, 2005.

86.

Mittwede

, Xiang

, Lu

, Clemmer

, and Hester

. Oxidative stress contributes to orthopedic trauma-induced acute kidney injury in obese rats. Am J Physiol Renal Physiol, 308: F157–F163, 2015.

87.

Mkaddem

, Werts

, Goujon

J-M

, Bens

, Pedruzzi

, Ogier-Denis

, and Vandewalle

. Heat shock protein gp96 interacts with protein phosphatase 5 and controls toll-like receptor 2 (TLR2)-mediated activation of extracellular signal-regulated kinase (ERK) 1/2 in post-hypoxic kidney cells. J Biol Chem, 284: 12541–12549, 2009.

88.

Monteiro

, Santos-Bezerra

, Thieme

, Admoni

, Perez

, Machado

, Queiroz

, Nery

, Oliveira-Souza

, Woronik

, Passarelli

, Giannella-Neto

, Machado

, and Corrêa-Giannella

. Thioredoxin interacting protein expression in the urinary sediment associates with renal function decline in type 1 diabetes. Free Radic Res, 50: 101–110, 2016.

89.

Mori

, Lee

, Rapoport

, Drexler

, Foster

, Yang

, Schmidt-Ott

, Chen

, Li

, Weiss

, Mishra

, Cheema

, Markowitz

, Suganami

, Sawai

, Mukoyama

, Kunis

, D'Agati

, Devarajan

, and Barasch

. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J Clin Invest, 115: 610–621, 2005.

90.

Murugan

and Kellum

. Acute kidney injury: what's the prognosis?. Nat Rev Nephrol, 7: 209–217, 2011.

91.

Nagasu

, Sogawa

, Kidokoro

, Itano

, Yamamoto

, Satoh

, Sasaki

, Suzuki

, Yamamoto

, Wigley

, Proksch

, Meyer

, and Kashihara

. Bardoxolone methyl analog attenuates proteinuria-induced tubular damage by modulating mitochondrial function. FASEB J Off Publ Fed Am Soc Exp Biol, 33: 12253–12263, 2019.

92.

Nezu

, Souma

, Yu

, Suzuki

, Saigusa

, Ito

, Suzuki

, and Yamamoto

. Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage progression. Kidney Int, 91: 387–401, 2017.

93.

Nishida

, Watanabe

, Miyahisa

, Hiramoto

, Nosaki

, Fujimura

, Maeda

, Otagiri

, and Maruyama

. Systemic and sustained thioredoxin analogue prevents acute kidney injury and its-associated distant organ damage in renal ischemia reperfusion injury mice. Sci Rep, 10: 20635, 2020.

94.

Nishida

, Watanabe

, Ogaki

, Kodama

, Tanaka

, Imafuku

, Ishima

, Chuang

VTG

, Toyoda

, Kondoh

, Wu

, Fukagawa

, Otagiri

, and Maruyama

. Renoprotective effect of long acting thioredoxin by modulating oxidative stress and macrophage migration inhibitory factor against rhabdomyolysis-associated acute kidney injury. Sci Rep, 5: 14471, 2015.

95.

Nishiyama

, Matsui

, Iwata

, Hirota

, Masutani

, Nakamura

, Takagi

, Sono

, Gon

, and Yodoi

. Identification of thioredoxin-binding protein-2/vitamin D(3) up-regulated protein 1 as a negative regulator of thioredoxin function and expression. J Biol Chem, 274: 21645–21650, 1999.

96.

Oberley

, Verwiebe

, Zhong

, Kang

, and Rhee

. Localization of the thioredoxin system in normal rat kidney. Free Radic Biol Med, 30: 412–424, 2001.

97.

Obrador

, Schultheiss

, Kretzler

, Langham

, Nangaku

, Pecoits-Filho

, Pollock

, Rossert

, Correa-Rotter

, Stenvinkel

, Walker

, Yang

C-W

, Fox

, and Köttgen

. Genetic and environmental risk factors for chronic kidney disease. Kidney Int Suppl, 7: 88–106, 2017.

98.

O'Connor

PM.

Renal oxygen delivery: matching delivery to metabolic demand. Clin Exp Pharmacol Physiol, 33: 961–967, 2006.

99.

O'Connor

, Anderson

, Kett

, and Evans

. Renal preglomerular arterial-venous O2 shunting is a structural anti-oxidant defence mechanism of the renal cortex. Clin Exp Pharmacol Physiol, 33: 637–641, 2006.

100.

Ogier

, Nayagam

, and Lockhart

. ASK1 inhibition: a therapeutic strategy with multi-system benefits. J Mol Med Berl Ger, 98: 335–348, 2020.

101.

Otaki

, Watanabe

, Takahashi

, Kadowaki

, Narumi

, Honda

, Wanezaki

, Sasaki

, Tamura

, Nishiyama

, Arimoto

, Shishido

, Miyamoto

, and Kubota

. Association of plasma thioredoxin-1 with renal tubular damage and cardiac prognosis in patients with chronic heart failure. J Cardiol, 64: 353–359, 2014.

102.

Papadopoulos

, Kinzler

, and Vogelstein

. The role of companion diagnostics in the development and use of mutation-targeted cancer therapies. Nat Biotechnol, 24: 985–995, 2006.

103.

Parikh

, Abraham

, Ancukiewicz

, and Edelstein

. Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit. J Am Soc Nephrol JASN, 16: 3046–3052, 2005.

104.

Park

, Lee

, Yi

, Kim

, Rhee

, and Woo

. Ablation of peroxiredoxin V exacerbates ischemia/reperfusion-induced kidney injury in mice. Antioxid Basel Switz, 9: 769, 2020.

105.

Paulsen

and Carroll

. Cysteine-mediated redox signaling: chemistry, biology, and tools for discovery. Chem Rev, 113: 4633–4679, 2013.

106.

Pei

, Zhang

, Peng

, Liu

, Zhang

, Yu

, Ma

, Huang

, Liu

, Yao

, Zeng

, and Xu

. Renal involvement and early prognosis in patients with COVID-19 pneumonia. J Am Soc Nephrol JASN, 31: 1157–1165, 2020.

107.

Perez

, Junnotula

, Knecht

, Nie

, Sanchez

, Boehm

, Booth-Genthe

, Yan

, Davis

, and Callahan

. Analytical approaches for quantification of a Nrf2 pathway activator: overcoming bioanalytical challenges to support a toxicity study. Analyst, 139: 1902–1912, 2014.

108.

Pergola

, Raskin

, Toto

, Meyer

, Huff

, Grossman

, Krauth

, Ruiz

, Audhya

, Christ-Schmidt

, Wittes

, and Warnock

. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med, 365: 327–336, 2011.

109.

Pokkunuri

, Lokhandwala

, and Banday

. Protein disulfide isomerase inhibition impairs Keap1/Nrf2 signaling and mitochondrial function and induces apoptosis in renal proximal tubular cells. Am J Physiol Renal Physiol, 319: F686–F696, 2020.

110.

Portilla

, Dent

, Sugaya

, Nagothu

, Kundi

, Moore

, Noiri

, and Devarajan

. Liver fatty acid-binding protein as a biomarker of acute kidney injury after cardiac surgery. Kidney Int, 73: 465–472, 2008.

111.

, Chen

, Gilbert

, Zhang

, Waltham

, Schache

, Kelly

, and Pollock

. High glucose-induced thioredoxin-interacting protein in renal proximal tubule cells is independent of transforming growth factor-beta1. Am J Pathol, 171: 744–754, 2007.

112.

, Chen

, Holian

, Tan

CYR

, Kelly

, and Pollock

. Transcription factors Krüppel-like factor 6 and peroxisome proliferator-activated receptor-{gamma} mediate high glucose-induced thioredoxin-interacting protein. Am J Pathol, 175: 1858–1867, 2009.

113.

Rabb

, Wang

, Nemoto

, Hotchkiss

, Yokota

, and Soleimani

. Acute renal failure leads to dysregulation of lung salt and water channels. Kidney Int, 63: 600–606, 2003.

114.

Redfors

, Bragadottir

, Sellgren

, Swärd

, and Ricksten

S-E

. Acute renal failure is NOT an “acute renal success”—a clinical study on the renal oxygen supply/demand relationship in acute kidney injury. Crit Care Med, 38: 1695–1701, 2010.

115.

Reid

JJ.

Endothelin-1 may be a physiologic modulator of vasoconstriction in rat kidney. J Cardiovasc Pharmacol 22(Suppl. 8): S267–S270, 1993.

116.

Remuzzi

, Ruggenenti

, and Perico

. Chronic renal diseases: renoprotective benefits of renin-angiotensin system inhibition. Ann Intern Med, 136: 604–615, 2002.

117.

Ronco

, Reis

, and Husain-Syed

. Management of acute kidney injury in patients with COVID-19. Lancet Respir Med, 8: 738–742, 2020.

118.

Rubartelli

, Bajetto

, Allavena

, Wollman

, and Sitia

. Secretion of thioredoxin by normal and neoplastic cells through a leaderless secretory pathway. J Biol Chem, 267: 24161–24164, 1992.

119.

Rundlöf

, Carlsten

, Giacobini

, and Arnér

. Prominent expression of the selenoprotein thioredoxin reductase in the medullary rays of the rat kidney and thioredoxin reductase mRNA variants differing at the 5’ untranslated region. Biochem J 347 Pt, 3: 661–668, 2000.

120.

Saeedi-Boroujeni

and Mahmoudian-Sani

M-R

. Anti-inflammatory potential of Quercetin in COVID-19 treatment. J Inflamm Lond Engl, 18: 3, 2021.

121.

Saito

, Suzuki

, Hiramoto

, Asami

, Naganuma

, Suda

, Iso

, Yamamoto

, Morita

, Baird

, Furusawa

, Negishi

, Ichinose

, and Yamamoto

. Characterizations of three major cysteine sensors of Keap1 in stress response. Mol Cell Biol, 36: 271–284, 2016.

122.

Santolini

, Wootton

, Jackson

, and Feelisch

. The Redox architecture of physiological function. Curr Opin Physiol, 9: 34–47, 2019.

123.

Sasaki

, Nishihira

, Ishibashi

, Yamasaki

, Obikane

, Echigoya

, Sado

, Ninomiya

, and Kobayashi

. Transgene of MIF induces podocyte injury and progressive mesangial sclerosis in the mouse kidney. Kidney Int, 65: 469–481, 2004.

124.

Sawa

, Akaike

, and Maeda

. Tyrosine nitration by peroxynitrite formed from nitric oxide and superoxide generated by xanthine oxidase. J Biol Chem, 275: 32467–32474, 2000.

125.

Sawa

, Zaki

, Okamoto

, Akuta

, Tokutomi

, Kim-Mitsuyama

, Ihara

, Kobayashi

, Yamamoto

, Fujii

, Arimoto

, and Akaike

. Protein S-guanylation by the biological signal 8-nitroguanosine 3’,5’-cyclic monophosphate. Nat Chem Biol, 3: 727–735, 2007.

126.

Scheel

, Liu

, and Rabb

. Uremic lung: new insights into a forgotten condition. Kidney Int, 74: 849–851, 2008.

127.

Schmidt

EE.

Interplay between cytosolic disulfide reductase systems and the Nrf2/Keap1 pathway. Biochem Soc Trans, 43: 632–638, 2015.

128.

Schrier

, Wang

, Poole

, and Mitra

. Acute renal failure: definitions, diagnosis, pathogenesis, and therapy. J Clin Invest, 114: 5–14, 2004.

129.

Schwartzman

, Liberman

, and Raz

. Bradykinin and angiotensin II activation of arachidonic acid deacylation and prostaglandin E2 formation in rabbit kidney. Hormone-sensitive versus hormone-insensitive lipid pools of arachidonic acid. J Biol Chem, 256: 2329–2333, 1981.

130.

Sedeek

, Callera

, Montezano

, Gutsol

, Heitz

, Szyndralewiez

, Page

, Kennedy

CRJ

, Burns

, Touyz

, and Hébert

. Critical role of Nox4-based NADPH oxidase in glucose-induced oxidative stress in the kidney: implications in type 2 diabetic nephropathy. Am J Physiol Renal Physiol, 299: F1348–F1358, 2010.

131.

Shah

, Xia

, Goldberg

, Lee

, Quaggin

, and Fantus

. Thioredoxin-interacting protein mediates high glucose-induced reactive oxygen species generation by mitochondria and the NADPH oxidase, Nox4, in mesangial cells. J Biol Chem, 288: 6835–6848, 2013.

132.

Shah

, Xia

, Masson

EAY

, Gui

, Momen

, Shikatani

, Husain

, Quaggin

, John

, and Fantus

. Thioredoxin-interacting protein deficiency protects against diabetic nephropathy. J Am Soc Nephrol JASN, 26: 2963–2977, 2015.

133.

Shi

, Lo

C-S

, Chenier

, Maachi

, Filep

, Ingelfinger

, Zhang

S-L

, and Chan

JSD

. Overexpression of catalase prevents hypertension and tubulointerstitial fibrosis and normalization of renal angiotensin-converting enzyme-2 expression in Akita mice. Am J Physiol Renal Physiol, 304: F1335–F1346, 2013.

134.

Sidhom

E-H

, Kim

, Kost-Alimova

, Ting

, Keller

, Avila-Pacheco

, Watts

, Vernon

, Marshall

, Reyes-Bricio

, Racette

, Wieder

, Kleiner

, Grinkevich

, Chen

, Weins

, Clish

, Shaw

, Quinzii

, and Greka

. Targeting a Braf/Mapk pathway rescues podocyte lipid peroxidation in CoQ deficiency kidney disease. J Clin Invest, 131: e141380, 2021.

135.

Son

, Kato

, Horibe

, Matsuo

, Mochizuki

, Mitsui

, Kawakami

, Nakamura

, and Yodoi

. Direct association of thioredoxin-1 (TRX) with macrophage migration inhibitory factor (MIF): regulatory role of TRX on MIF internalization and signaling. Antioxid Redox Signal, 11: 2595–2605, 2009.

136.

Song

, Qiu

, Shi

, Wang

, Zhou

, Chen

, Wei

, Wu

, and Duan

Thioredoxin-interacting protein deficiency alleviates phenotypic alterations of podocytes via inhibition of mTOR activation in diabetic nephropathy. J Cell Physiol 2019 [Online ahead of print], DOI: 10.1002/jcp.28317.

137.

Stryer

, Holmgren

, and Reichard

. Thioredoxin. A localized conformational change accompanying reduction of the protein to the sulfhydryl form. Biochemistry, 6: 1016–1020, 1967.

138.

Sumbayev

VV.

S-nitrosylation of thioredoxin mediates activation of apoptosis signal-regulating kinase 1. Arch Biochem Biophys, 415: 133–136, 2003.

139.

Sung

C-C

, Hsu

Y-C

, Chen

C-C

, Lin

Y-F

, and Wu

C-C

. Oxidative stress and nucleic acid oxidation in patients with chronic kidney disease. Oxid Med Cell Longev, 2013: 301982, 2013.

140.

Tan

CYR

, Weier

, Zhang

, Cox

, Kelly

, and Langham

. Thioredoxin-interacting protein: a potential therapeutic target for treatment of progressive fibrosis in diabetic nephropathy. Nephron, 129: 109–127, 2015.

141.

Tan

, Zhou

, Xiao

, Zhou

, Li

, Bastacky

, Oury

, and Liu

. Extracellular superoxide dismutase protects against proteinuric kidney disease. J Am Soc Nephrol JASN, 26: 2447–2459, 2015.

142.

Tan

, Zhang

, Cox

, Kelly

, and Qi

. Tranilast attenuates the up-regulation of thioredoxin-interacting protein and oxidative stress in an experimental model of diabetic nephropathy. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc Eur Ren Assoc, 26: 100–110, 2011.

143.

Tanaka

, Tanaka

, and Nangaku

. Hypoxia as a key player in the AKI-to-CKD transition. Am J Physiol-Ren Physiol, 307: F1187–F1195, 2014.

144.

Tanaka

, Tanaka

, and Nangaku

. Hypoxia and dysregulated angiogenesis in kidney disease. Kidney Dis Basel Switz, 1: 80–89, 2015.

145.

Tanaka

, Nishiyama

, Okada

, Hirota

, Matsui

, Yodoi

, Hiai

, and Toyokuni

. Induction and nuclear translocation of thioredoxin by oxidative damage in the mouse kidney: independence of tubular necrosis and sulfhydryl depletion. Lab Investig J Tech Methods Pathol, 77: 145–155, 1997.

146.

Tchouagué

, Grondin

, Glory

, and Averill-Bates

. Heat shock induces the cellular antioxidant defenses peroxiredoxin, glutathione and glucose 6-phosphate dehydrogenase through Nrf2. Chem Biol Interact, 310: 108717, 2019.

147.

Terada

, Inoshita

, Kuwana

, Kobayashi

, Okado

, Ichijo

, and Sasaki

. Important role of apoptosis signal-regulating kinase 1 in ischemic acute kidney injury. Biochem Biophys Res Commun, 364: 1043–1049, 2007.

148.

Tesch

, Ma

, and Nikolic-Paterson

. ASK1: a new therapeutic target for kidney disease. Am J Physiol Renal Physiol, 311: F373–F381, 2016.

149.

Thieme

, Pereira

BMV

, da Silva

, Fabre

, Catanozi

, Passarelli

, and Correa-Giannella

. Chronic advanced-glycation end products treatment induces TXNIP expression and epigenetic changes in glomerular podocytes in vivo and in vitro . Life Sci, 270: 118997, 2021.

150.

Tobino

, Muso

, Iwasaki

, Yonemoto

, Kasuno

, Tsukamoto

, Nakamura

, and Tomino

. Gender- and disease-specific urinary thioredoxin in chronic kidney disease patients with or without type 2 diabetic nephropathy. Nephrol Carlton Vic, 20: 368–374, 2015.

151.

Tran

, Zsengeller

, Berg

, Khankin

, Bhasin

, Kim

, Clish

, Stillman

, Karumanchi

, Rhee

, and Parikh

. PGC1α-dependent NAD biosynthesis links oxidative metabolism to renal protection. Nature, 531: 528–532, 2016.

152.

Tripatara

, Patel

NSA

, Collino

, Gallicchio

, Kieswich

, Castiglia

, Benetti

, Stewart

, Brown

PAJ

, Yaqoob

, Fantozzi

, and Thiemermann

. Generation of endogenous hydrogen sulfide by cystathionine gamma-lyase limits renal ischemia/reperfusion injury and dysfunction. Lab Investig J Tech Methods Pathol, 88: 1038–1048, 2008.

153.

Wang

and Zhao

S-M

. LncRNA-antisense non-coding RNA in the INK4 locus promotes pyroptosis via miR-497/thioredoxin-interacting protein axis in diabetic nephropathy. Life Sci, 264: 118728, 2021.

154.

Weaver

, Fadrowski

, and Jaar

BG.

Global dimensions of chronic kidney disease of unknown etiology (CKDu): a modern era environmental and/or occupational nephropathy? BMC Nephrol 16, 2015.

155.

Wei

, Shi

, Hou

, Ren

, Du

, Zhang

, Li

, and Duan

. Knockdown of thioredoxin-interacting protein ameliorates high glucose-induced epithelial to mesenchymal transition in renal tubular epithelial cells. Cell Signal, 25: 2788–2796, 2013.

156.

Weisbord

and Palevsky

. Kidney injury after contrast media: marker or mediator?. Nat Rev Nephrol, 6: 634–636, 2010.

157.

Whiteman

, Gooding

, Whatmore

, Ball

, Mawson

, Skinner

, Tooke

, and Shore

. Adiposity is a major determinant of plasma levels of the novel vasodilator hydrogen sulphide. Diabetologia, 53: 1722–1726, 2010.

158.

Woodcock

The prospects for “personalized medicine” in drug development and drug therapy. Clin Pharmacol Ther, 81: 164–169, 2007.

159.

C-L

, Su

T-C

, Chang

C-C

, Kor

C-T

, Chang

C-H

, Yang

T-H

, Chiu

P-F

, and Tarng

D-C

. Tubular peroxiredoxin 3 as a predictor of renal recovery from acute tubular necrosis in patients with chronic kidney disease. Sci Rep, 7: 43589, 2017.

160.

, Li

, Hou

, Song

, Han

, Chen

, Du

, Ren

, and Shi

. Thioredoxin-interacting protein deficiency ameliorates kidney inflammation and fibrosis in mice with unilateral ureteral obstruction. Lab Investig J Tech Methods Pathol, 98: 1211–1224, 2018.

161.

, Siow

, and O K. Ischemia/reperfusion reduces transcription factor Sp1-mediated cystathionine beta-synthase expression in the kidney. J Biol Chem, 285: 18225–18233, 2010.

162.

Wuttke

and Köttgen

. Insights into kidney diseases from genome-wide association studies. Nat Rev Nephrol, 12: 549–562, 2016.

163.

Xiao

, Huang

, Wang

, Wu

, Leng

, Liu

, Sun

, and Xia

Z-Y

. Thioredoxin-interacting protein mediates NLRP3 inflammasome activation involved in the susceptibility to ischemic acute kidney injury in diabetes. Oxid Med Cell Longev, 2016: 2386068, 2016.

164.

Yadav

, Martinov

, Vitvitsky

, Seravalli

, Wedmann

, Filipovic

, and Banerjee

. Biosynthesis and reactivity of cysteine persulfides in signaling. J Am Chem Soc, 138: 289–299, 2016.

165.

Yamamoto

, Tada

, Brodsky

, Tanaka

, Noiri

, Kajiya

, and Goligorsky

. Intravital videomicroscopy of peritubular capillaries in renal ischemia. Am J Physiol Renal Physiol, 282: F1150–F1155, 2002.

166.

Yang

, Besschetnova

, Brooks

, Shah

, and Bonventre

. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med, 16: 535–543, 2010.

167.

Yin

, Wheeler

, Connor

, Zhong

, Bunzendahl

, Dikalova

, Samulski

, Schoonhoven

, Mason

, Swenberg

, and Thurman

. Cu/Zn-superoxide dismutase gene attenuates ischemia-reperfusion injury in the rat kidney. J Am Soc Nephrol JASN, 12: 2691–2700, 2001.

168.

Yokoi

, Kasuno

, Nishimori

, Nishikawa

, Morita

, Kobayashi

, Fukushima

, Mikami

, Takahashi

, Oota

, Kimura

, Soya

, Kimata

, Nishimura

, Ono

, Muso

, Yoshida

, Yodoi

, and Iwano

. Analytical and clinical validation of rapid chemiluminescence enzyme immunoassay for urinary thioredoxin, an oxidative stress-dependent early biomarker of acute kidney injury. Clin Chim Acta Int J Clin Chem, 507: 271–279, 2020.

169.

Zhang

and Hannink

. Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol, 23: 8137–8151, 2003.

170.

Zhang

and Lu

. Ifosfamide induces acute renal failure via inhibition of the thioredoxin reductase activity. Free Radic Biol Med, 43: 1574–1583, 2007.

171.

Zhang

, Wang

P-X

, Zhao

L-P

, Zhang

, Ji

Y-X

, Zhang

X-J

, Fang

, Lu

Y-X

, Yang

, Gao

M-M

, Zhang

, Tian

, Zhu

X-Y

, Gong

, Ma

X-L

, Li

, Wang

, Huang

, She

Z-G

, and Li

. The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis. Nat Med, 24: 84–94, 2018.

172.

Zhou

, Tardivel

, Thorens

, Choi

, and Tschopp

. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol, 11: 136–140, 2010.