Potential Therapeutic Targets of Obesity-Related Glomerulopathy

Abstract

The global increase of obesity parallels the obesity-related glomerulopathy (ORG) epidemic. The purpose of this review is to emphasize the potential therapeutic targets of ORG as well as the corresponding possible mechanisms. We systematically identified surveys, reports, and published studies that included data for the purpose of this review and did literature analysis. Under circumstance of obesity, weight loss, and renin–angiotensin–aldosterone blockade are the most studied therapies, effective to induce antiproteinuric effects and reversal of hyperfiltration in ORG. Glucagon-like peptide-1-based therapies led to improvement in proteinuria. Newer therapies directed to lipid metabolism, including farnesoid X receptor and takeda G protein–coupled receptor 5 agonists, peroxisome proliferator-activated receptor α agonists, hold therapeutic promise. Prevention and treatments of obesity and ORG are of great importance.

Introduction

The rising prevalence of overweight and obesity has been described as a global pandemic. The proportion of adults worldwide with a body mass index of 25 kg/m² or greater increased from 28.8% to 36.9% in men, and from 29.8% to 38.0% in women between 1980 and 2013.¹ The Centers for Disease Control and Prevention stated that 34.8% of US adults suffer from obesity, affecting 93.3 million US adults from 2015 to 2016 (https://www.cdc.gov/obesity/data/adult.html). In China, the proportion of the overweight and obesity among adults was 30.1% and 11.9%, respectively, in 2015.² Concerns about the corresponding health problems associated with obesity have become universal.

Obesity has direct effects on the development of chronic kidney disease (CKD) and end-stage renal disease (ESRD) and increases the risk of developing diabetes and hypertension. Obesity not only increases the risk of progression of pre-existing renal diseases but is itself also an independent risk factor of renal injury. Obesity widespread has increased incidence of obesity-related glomerulopathy (ORG), featuring proteinuria, glomerulomegaly, progressive glomerulosclerosis, and renal functional decline. Most patients with ORG have stable or slowly progressive proteinuria, up to one-third develop progressive renal failure and ESRD.

In this study, we review the potential therapeutic targets of ORG as well as the corresponding possible mechanisms. As in other chronic proteinuric nephropathies, a significant reduction in proteinuria is assumed to have a renoprotective effect in ORG. The final aim is to slow down estimated glomerular filtration rate (eGFR) decline to delay ESRD progression.

Weight Loss

The effects of weight loss, either by behavioral intervention or bariatric surgery (BS), in the obesity with proteinuria have been evaluated in various studies.^3

–10 The most important finding was that weight loss was accompanied by a significant reduction of proteinuria, the greater the weight loss the greater the reduction in proteinuria. The antiproteinuric effect of weight loss in the obese patients was also obvious in other nephropathies.¹¹ The levels of serum creatinine and/or GFR were often improved meanwhile.^{4

–7,9,10,12,13} But it was also observed a trend toward a favorable effect of weight loss on GFR rather than a significant change.¹⁴

Bariatric surgeries include Roux-en-Y gastric bypass, adjustable gastric banding, and sleeve gastrectomy. Patients, who needed bariatric surgeries, had more severe obesity than dietary intervention patients. Previous studies proved weight loss with BS to be much more effective than with low-calorie diets and independent of surgical procedure.^5,8,9 However, BS may be followed by renal complications, such as nephrolithiasis (common),¹⁵ acute kidney injury,¹⁶ and oxalate nephropathy (rare).¹⁷ Moreover, the incidence of postoperative complications increased with CKD stage.

The reason why proteinuria was repressed by weight loss may include the reduction of systematic and renal inflammation^5,6 (adipokines involved), the improvements of hypertension,^5,7 dyslipidemia,^6,7 and insulin resistance^7,18 concomitantly.

Renin–Angiotensin–Aldosterone Blockade

Renin–angiotensin–aldosterone (RAAS) blockade is currently the recommended first-line treatment for proteinuric diabetic or nondiabetic nephropathy. Under circumstance of obesity, the RAAS is overactivated and levels of RAAS components are increased in the circulation and in renal tissue. Various studies have demonstrated that RAAS blockade, by angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), is thought effective to induce antiproteinuric effects and reversal of hyperfiltration in ORG. The renoprotective effects might be more remarkable in obese patients than in nonobese patients and may persist less consistently when compared with weight loss.¹⁹

Besides the aforementioned RAAS blockers, mineralocorticoid-receptor antagonists (MRAs) also matter, No funding was received for this review.although very few studies have addressed the effects of MRAs on the renal complications of obesity. A short-term study (4 weeks) showed that the addition of spironolactone to an ACEI reduced albuminuria in obese patients.²⁰ Another longer-term study (28.9 months) showed that spironolactone added to traditional RAAS blockers induced a drastic and sustained reduction in proteinuria in obese patients with proteinuric nephropathies but not more than the nonobese group.²¹ The antiproteinuric effect of spironolactone may vary according to the degree of albuminuria, impaired eGFR, and aldosterone escape.²² But hyperkalemia may limit its use. The long-term effects of spironolactone add-on on renal outcomes and mortality need to be studied.

The RAAS blockade may reduce proteinuria through its hemodynamic effects. In physiological conditions, angiotensin II (Ang II) and aldosterone constrict efferent arterioles more specifically than afferent arterioles and further increase transcapillary hydraulic pressure difference and GFR. Ang II can directly activate mineralocorticoid receptors and promote sodium reabsorption. It can also be achieved by stimulation of the luminal Na⁺⁻H⁺ exchanger and the basolateral Na⁺⁻K⁺-ATPase proximally, and by activation of the epithelial Na⁺ channel distally. In obesity cases, RAAS is overactivated and thus may act as an effect factor for hypertension and renal hyperfiltration.

Few studies have addressed possible antiproteinuric mechanisms of MRAs. Wnt/β-catenin signaling in podocytes serves a crucial role in integrating cell adhesion, motility, differentiation, and survival. Accumulating evidence has suggested that activation of Wnt/β-catenin signaling pathway induces proteinuria and podocyte dysfunction. Zhu et al. have demonstrated that aldosterone is involved in the pathogenesis of ORG through activation of Wnt/β-catenin signaling in podocytes.²³ Rho-kinase activation elicits myofibroblastic transformation in renal cells and contributes to the progression of renal fibrosis. Mineralocorticoid receptor activation in the kidney tissue and the subsequent Rho-kinase stimulation are likely to participate in the development of obesity-associated nephropathy without elevation in serum aldosterone levels.²⁴

Glucagon-Like Peptide-1-Based Therapies

Glucagon-like peptide-1 (GLP-1)-based therapies, GLP-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase 4 (DPP4) inhibitors have been widely studied and used in diabetes area. This kind of therapies may exert beneficial effects on traditional risk factors for CKD, for example, through lowering glucose and blood pressure (BP), decreasing insulin levels, and causing weight loss.²⁵ GLP-1 has been demonstrated to induce natriuresis and diuresis, likely involving the inhibition of the sodium–hydrogen exchanger 3 (NHE3) localized at the brush border of the renal proximal tubular cells.²⁶ This effect may partially explain the BP-lowering effects of GLP-1RAs. Some DPP-4 inhibitors could inhibit ACE activity and reduce Ang II levels.²⁷ This could partially explain the renal effects of these drugs.

In obesity-related disorders, various studies have demonstrated that GLP-1-based therapies led to improvement in proteinuria. The pleiotropic actions of these drugs are well reported.

Baseline DPP-4 activity was an independent predictive factor for proteinuria onset.²⁸ GLP-1-based treatments improved renal vascular damage through alleviated uncoupling of the glomerular endothelial growth factor-nitric oxide axis,²⁹ improved NO-mediated dilation of small intrarenal arteries and arterioles, and a reduction in renal inflammation.^30,31 GLP-1 reduced urinary albumin excretion in ORG by improving podocyte damage. The mechanism may be partly associated with the inhibition of tumor necrosis factor-mediated nuclear factor (NF)-kB and mitogen-activated protein kinase pathways,³² attenuated translocation of glucose transport factor 4 to the plasma membrane followed by decreased level of podocyte autophagy,³³ and decreased podocyte apoptosis by inhibition of the receptor for advanced glycation endproducts (RAGEs).³⁴

GLP-1RAs inhibit AGE-induced RAGE expressions and mesangial cell death. The renoprotective effects may be due to the anti-inflammatory and antioxidative effects.³⁵ GLP-1 analog exerted renoprotective effects against saturated fatty acid-induced kidney tubular cell endoplasmic reticulum stress and apoptosis together with inhibition of Ang II type 1 receptor (AT1R) expression in vivo and in vitro.³⁶ Meanwhile, DPP-4 inhibition has been indicated to protect proximal tubular cells against proteinuria induced by free fatty acid-bound albumin in vivo and in vitro.³⁷ Besides, high fat diet (HFD)-induced kidney injury was alleviated at least partly through directly restoring renal metabolism.³⁸

Farnesoid X-Activated Receptor Agonists

Farnesoid X receptor (FXR) is a nuclear bile acid (BA) receptor and is activated by primary BAs such as chenodeoxycholic acid (CDCA), cholic acid, and synthetic agonists such as obeticholic acid. FXR agonists constitute possible nephroprotective drugs with the potential to repair renal tissue damage.³⁹ In vivo study on models of diabetic or obesity-related nephropathy, FXR is demonstrated favorable in terms of proteinuria, podocyte loss, mesangial expansion, and tubulointerstitial fibrosis.^40,41 In fructose-fed Wistar rats, FXR agonist CDCA modulates renal lipid metabolism, decreases proteinuria and improves renal fibrosis, inflammation, and oxidation stress.⁴² Obeticholic acid pretreatment protects against sepsis-induced acute kidney injury through inhibiting renal inflammation and oxidative stress.⁴³

FXR plays a crucial role in regulating lipid and glucose metabolism, oxidative stress, and inflammation. The renal benefit from FXR's systemic effects (on blood glucose, fatty acid and BA levels, and the vasculature) is less clear-cut than the benefit from its direct renal effects.³⁹ In renal disease, FXR mediates direct antilipogenic, anti-inflammatory, antifibrotic, and antioxidant effects within the renal parenchyma. FXR negatively regulates sterol regulatory element binding protein-1 (SREBP-1) mediating lipid accumulation and decreased expression of proinflammatory cytokines and profibrotic growth factors. FXR agonists inhibit SREBP-1 expression, lipid accumulation, inflammation, and fibrosis in animal models of diet-induced obesity.¹⁹

Takeda G Protein–Coupled Receptor 5 Agonists

Besides the nuclear receptor FXR, another receptor for BA has also been identified highly expressed in the kidney: the membrane-bound, G protein-coupled bile acid receptor 1 (GPBAR1, also known as takeda G protein–coupled receptor 5 [TGR5]).

CDCA attenuates HFD-induced obesity and hyperglycemia through TGR5 and peroxisome proliferator-activated receptor γ (PPARγ) pathway.⁴⁴ Low levels of TGR5 mRNA were associated with kidney disease progression, as evidenced by inverse correlations with glomerulosclerosis, proteinuria and decline in eGFR, and direct correlations with expression of podocyte markers. TGR5 agonist INT-777 enhanced mitochondrial function, prevented weight gain, and reduced renal lipid accumulation in diet-induced obesity mice.⁴⁵ Treatment of diabetic DBA/2J and db/db mice with the dual FXR/TGR5 agonist INT-767 improved proteinuria and prevented podocyte injury, mesangial expansion, and tubulointerstitial fibrosis.⁴⁰

Numerous studies have demonstrated that TGR5 exhibits effective regulation of glucose and lipid metabolism, energy homeostasis, and anti-inflammatory effects.

TGR5 activation leads to increases in mitochondrial oxidative phosphorylation, mitochondrial fatty acid β-oxidation and mitochondrial superoxide dismutase activity, inhibition of mitochondrial reactive oxygen species generation, and anti-inflammatory actions of the receptor in the kidney.⁴⁶ TGR5 antagonized kidney inflammation at least in part by inhibiting NF-κB and signal transducer and activator of transcription 3 signaling.⁴⁷ TGR5 activation suppressed sphingosine 1-phosphate (S1P)/sphingosine 1-phosphate receptor 2 (S1P2) signaling and resisted high glucose-induced fibrosis in glomerular mesangial cells.⁴⁸ Besides, TGR5 modulators are expected to be useful partly because of their capacity to release GLP-1,⁴⁶ a well-known target for the treatment of diabetes and obesity.

In addition, some traditional agents, such as fibrates (PPARα agonists), could also reduce progression of albuminuria, which has been demonstrated by several large-scale studies.^49,50 PPARα is activated to increase fatty acid β-oxidation in ORG, which leads to less triglyceride accumulation in the kidney.

To sum up, obesity increased incidence of ORG. ORG patients have stable or progressive proteinuria, possibly progressing toward renal failure and ESRD. Therefore, treatments to reduce proteinuria in ORG were included in this review. In most cases, we selected original articles focused on each therapeutic coupled with obesity-related kidney damage. We stated most studied therapeutics as shown in the frame (Fig. 1). It contains each therapeutic and the possible corresponding mechanisms to reduce proteinuria.

FIG. 1.

Potential therapeutic targets of ORG and the corresponding possible mechanisms. ACEI, angiotensin-converting enzyme inhibitor; Ang II, angiotensin II; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; FXR, farnesoid X receptor; GLP-1, glucagon-like peptide-1; IR, insulin resistance; MRA, mineralocorticoid-receptor antagonist; ORG, obesity-related glomerulopathy; PPAR, peroxisome proliferator-activated receptor; RAAS, renin–angiotensin–aldosterone; TGR5, takeda G protein–coupled receptor 5.

Conclusion

As the epidemic of obesity continues to increase, ORG will become an even greater problem. Prevention and treatments of obesity and ORG are of great importance. As clinicians gain greater insight into the pathophysiology of obesity and its related issues, including ORG, it is hoped that new and better tools will be developed to treat it.

Footnotes

Author Disclosure Statement

No conflicting financial interests exist.

Funding Information

No funding was received for this review.

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