Hypoxia has adverse effects on renal development. This study was the first to test hypoxia-induced renal autophagy in rat fetuses.
Methods:
Pregnant rats were exposed to hypoxia or normoxia during pregnancy and fetal kidneys were collected at gestation day 21.
Results:
Fetal kidney weight and ratio of kidney–body weight were reduced. Histological analysis showed enlargement in Bowman space and wider space between interstitia in the kidneys of fetus exposed to hypoxia. Fetal renal B-cell lymphoma 2 (BCL-2) was decreased accompanied with higher 2′-deoxyuridine 5′-triphosphate nick end-labeling staining and unchanged soluble FAS in the hypoxia group. Hypoxia increased autophagic structures, including autophagosomes and autolysosomes, in fetal kidneys and increased renal APG5L. There was an increase in renal LC3-II, Beclin 1, p-S6, hypoxia inducible factor 1α (HIF-1a), and ratio of LC3-II–LC3-I and a decrease in P62, protein kinase B (AKT), and phosphorylated AKT in the hypoxia group. Both renal mammalian target of rapamycin (mTOR) and Beclin 1 signaling were upregulated.
Conclusion:
Hypoxia-affected fetal renal development was associated with renal apoptosis and Beclin 1 signaling-mediated autophagy.
TapanainenPJBangPWilsonKUntermanTGVremanHJRosenfeldRG. Maternal hypoxia as a model for intrauterine growth retardation: effects on insulin-like growth factors and their binding proteins. Pediatr Res. 1994;36(2):152–158.
2.
PeyronnetJDalmazYEhrstromM. Long lasting adverse effects of prenatal hypoxia on developing autonomic nervous system and cardiovascular parameters in rats. Pflugers Arch. 2002;443(5-6):858–865.
3.
ReamMRayAMChandraRChikaraishiDM. Early fetal hypoxia leads to growth restriction and myocardial thinning. Am J Physiol Regul Integr Comp Physiol. 2008;295(2):R583–R595.
4.
XueQZhangL. Prenatal hypoxia causes a sex-dependent increase in heart susceptibility to ischemia and reperfusion injury in adult male offspring: role of protein kinase C epsilon. J Pharmacol Exp Ther. 2009;330(2):624–632.
5.
Rueda-ClausenCFDolinskyVWMortonJSProctorSDDyckJRDavidgeST. Hypoxia-Induced intrauterine growth restriction increases the susceptibility of rats to high-fat diet-induced metabolic syndrome. Diabetes. 2011;60(2):507–516.
6.
HickeyRJClellandRCBowersEJ. Maternal smoking, birth weight, infant death, and the self-selection problem. Am J Obstet Gynecol. 1978;131(7):805–811.
7.
CogswellMEYipR. The influence of fetal and maternal factors on the distribution of birth weight. Semin Perinatol. 1995;19(3):222–240.
8.
MooreLGBrodeurPChumbeOD’BrotJHofmeisterSMongeC. Maternal hypoxic ventilatory response, ventilation and birth weight at 4,300 m. J Appl Physiol. 1986;60(4):1401–1406.
9.
RegnaultTRHVrijerBDGalanHLWilkeningRBBattagliaFCMeschiaG. Development and mechanisms of fetal hypoxia in severe fetal growth restriction. Placenta. 2007;28(7):714–723.
10.
MaoCPHouJQGeJY. Changes of renal AT 1/AT 2 receptors and structures in ovine fetuses following exposure to long-term hypoxia. Am J Nephrol. 2010;31(2):141–150.
11.
Gonzalez-RodriguezPJTongWXueQLiYHuSZhangLV. Fetal hypoxia results in programming of aberrant angiotensin II receptor expression patterns and kidney development. Int J Med Sci. 2013;10(5):532–538.
12.
AllamHIRahmanTA. The protective role of adrenomedullin and anti-tumor necrosis factor on some vasoregulatory factors and renal functions in hypertensive pregnant rats. Kingdom of Saudi Arabia King Abdulaziz City for Science and Technology General Directorate of Research Grants Programs LGP-10-19 final report. 2009:43–78.
13.
Langley-EvansSCWelhamSJJacksonAA. Fetal exposure to a maternal low protein diet impairs nephrogenesis and promotes hypertension in the rat. Life Sci. 1999;64(11):965–974.
14.
LloydLJFosterTRhodesPRhindSMGardnerDS. Protein-energy malnutrition during early gestation in sheep blunts fetal renal vascular and nephron development and compromises adult renal function. J Physiol. 2012;590(pt 2):377–393.
15.
KosekiCHerzlingerDAl-AwqatiQ. Apoptosis in metanephric development. J Cell Biol. 1992;119(5):1327–1333.
16.
WelhamSJWadeAWoolfAS. Protein restriction in pregnancy is associated with increased apoptosis of mesenchymal cells at the start of rat metanephrogenesis. Kidney Int. 2002;61(4):1231–1242.
17.
DziarmagaAEcclesMGoodyerP. Suppression of ureteric bud apoptosis rescues nephron endowment and adult renal function in Pax2 mutant mice. J Am Soc Nephrol. 2006;17(6):1568–1575.
18.
NarlisMGroteDGaitanYBoualiaSKBouchardM. Pax2 and Pax8 regulate branching morphogenesis and nephron differentiation in the developing kidney. J Am Soc Nephrol. 2007;18(4):1121–1129.
19.
ThorburnA. Apoptosis and autophagy: regulatory connections between two supposedly different processes. Apoptosis. 2008;13(1):1–9.
20.
ColesHSBurneJFRaffMC. Large-scale normal cell death in the developing rat kidney and its reduction by epidermal growth factor. Development. 1993;118(3):777–784.
21.
SorensonCM. Life, death and kidneys: regulation of renal programmed cell death. Curr Opin Nephrol Hypertens. 1998;7(1):5–12.
22.
WoolfASWelhamSJ. Cell turnover in normal and abnormal kidney development. Nephrol Dial Transplant. 2002;17(suppl 9):2–4.
23.
PhamTDMacLennanNKChiuCTLaksanaGSHsuJLLaneRH. Uteroplacental insufficiency increases apoptosis and alters p53 gene methylation in the full-term IUGR rat kidney. Am J Physiol. 2003;285:R962–R970.
24.
HeCCKlionskyDJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009;43:67–93.
25.
ShiLJMaoCPWuJWMorrisseyPLeeJXXuZC. Effects of i.c.v. losartan on the angiotensin II-mediated vasopressin release and hypothalamic fos expression in near-term ovine fetuses. Peptides. 2006;27(9):2230–2238.
26.
YangWLMaoCPXiaF. Changed salt appetite and central angiotensin II-induced cellular activation in rat offspring following hypoxia during fetal stages. Peptides. 2010;31(6):1177–1183.
27.
MurotsukiJChallisJRHanVKFraheLJGagnonR. Chronic fetal placental embolization and hypoxemia cause hypertension and myocardial hypertrophy in fetal sheep. Am J Physiol. 1997;272(1 pt 2):R201–R207.
28.
LuziGBoriSIammarinoG. Functional aspects of the fetal urinary apparatus in relation to growth. Arch Ital Urol Androl. 1996;68(5 suppl):9–12.
29.
VehaskariVMAvilesDHManningJ. Prenatal programming of adult hypertension in the rat. Kidney Int. 2001;59(1):238–245.
30.
WelhamSJWadeAWoolfAS. Protein restriction in pregnancy is associated with increased apoptosis of mesenchymal cells at the start of rat metanephrogenesis. Kidney Int. 2002;61:1231–1242.
31.
LeBrunDPWarnkeRAClearyML. Expression of bcl-2 in fetal tissues suggests a role in morphogenesis. Am J Pathol. 1993;142(3):743–753.
32.
LeePSataMLeferDJFactorSMWalshKKitsisRN. Fas pathway is a critical mediator of cardiac myocyte death and myocardial infarction during ischemia–reperfusion in vivo. Am J Physiol Heart Circ Physiol. 2003;284(2):H456–H463.
33.
MizushimaNLevineBCuervoAMKlionskyDJ. Autophagy fights disease through cellular self-digestion. Nature. 2008;451(7182):1069–1075.
34.
RubinszteinDC. The roles of intracellular protein degradation pathways in neurodegeneration. Nature. 2006;443(7113):780–786.
35.
MizushimaNYoshimoriTLevineB. Methods in mammalian autophagy research. Cell. 2010;140(3):313–326.
36.
IchimuraYKumanomidouTSouYS. Structural basis for sorting mechanism of p62 in selective autophagy. J Biol Chem. 2008;283(33):22847–22857.
37.
Ylä-AnttilaPVihinenHJokitaloEEskelinenEL. Monitoring autophagy by electron microscopy in Mammalian cells. Methods Enzymol. 2009;452:143–164.
38.
CodognoPMeijerAJ. Atg5: more than an autophagy factor. Nat Cell Biol. 2006;8(10):1045–1047.
39.
MatsushitaMSuzukiNNObaraKFujiokaYOhsumiYInagakiF. Structure of Atg5·Atg16, a complex essential for autophagy. J Biol Chem. 2007;282(9):6763–6772.
40.
ClarkRSBayirHChuCTAlberSMKochanekPMWatkinsSC. Autophagy is increased in mice after traumatic brain injury and is detectable in human brain after trauma and critical illness. Autophagy. 2008;4(1):88–90.
41.
MaiuriMCLe ToumelinGCriolloA. Functional and physical interaction between Bcl-XL and a BH3-like domain in Beclin-1. EMBO J. 2007;26(10):2527–2539.
42.
ObersteinAJeffreyPDShiYG. Crystal structure of the Bcl-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J Biol Chem. 2007;282(17):13123–13132.
43.
MaiuriMCCriolloATasdemirE. BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin-1 and Bcl-2/Bcl-X(L). Autophagy. 2007;3(4):374–376.
44.
ZhangHFBosch-MarceMShimodaLA. Mitochondrial autophagy is an HIF-1-dependent adaptive etabolic response to hypoxia. J Biol Chem. 2008;283(16):10892–10903.
45.
NodaTOhsumiY. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem. 1998;273(7):3963–3966.
46.
WullschlegerSLoewithRHallMN. TOR signaling in growth and metabolism. Cell. 2006;124(3):471–484.
47.
CodognoPMeijerAJ. Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ. 2005;12Suppl 2:1509–1518.
48.
HayNSonenbergN. Upstream and downstream of mTOR. Genes Dev. 2004;18(16):1926–1945.
49.
GozuacikDBialikSRavehT. DAP-kinase is a mediator of endoplasmic reticulum stress-induced caspase activation and autophagic cell death. Cell Death Differ. 2008;15(12):1875–1886.
50.
LevineBYuanJ. Autophagy in cell death: an innocent convict?J Clin Invest. 2005;115(10):2679–2688.
51.
MaiuriMCZalckvarEKimchiAKroemerG. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 2007;8(9):741–752.
