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Prenatal Exposure to Hypoxia Induced Beclin 1 Signaling-Mediated Renal Autophagy and Altered Renal Development in Rat Fetuses

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Abstract

Aims: 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.

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References

  1. Tapanainen PJ, Bang P, Wilson K, Unterman TG, Vreman HJ, Rosenfeld RG. 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.

    Article  CAS  PubMed  Google Scholar 

  2. Peyronnet J, Dalmaz Y, Ehrstrom M, et al. 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.

    Article  CAS  PubMed  Google Scholar 

  3. Ream M, Ray AM, Chandra R, Chikaraishi DM. Early fetal hypoxia leads to growth restriction and myocardial thinning. Am J Physiol Regul Integr Comp Physiol. 2008;295(2):R583–R595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Xue Q, Zhang L. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rueda-Clausen CF, Dolinsky VW, Morton JS, Proctor SD, Dyck JR, Davidge ST. Hypoxia-Induced intrauterine growth restriction increases the susceptibility of rats to high-fat diet-induced metabolic syndrome. Diabetes. 2011;60(2):507–516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hickey RJ, Clelland RC, Bowers EJ. Maternal smoking, birth weight, infant death, and the self-selection problem. Am J Obstet Gynecol. 1978;131(7):805–811.

    Article  CAS  PubMed  Google Scholar 

  7. Cogswell ME, Yip R. The influence of fetal and maternal factors on the distribution of birth weight. Semin Perinatol. 1995;19(3):222–240.

    Article  CAS  PubMed  Google Scholar 

  8. Moore LG, Brodeur P, Chumbe O, D’Brot J, Hofmeister S, Monge C. Maternal hypoxic ventilatory response, ventilation and birth weight at 4,300 m. J Appl Physiol. 1986;60(4):1401–1406.

    Article  CAS  PubMed  Google Scholar 

  9. Regnault TRH, Vrijer BD, Galan HL, Wilkening RB, Battaglia FC, Meschia G. Development and mechanisms of fetal hypoxia in severe fetal growth restriction. Placenta. 2007;28(7):714–723.

    Article  CAS  PubMed  Google Scholar 

  10. Mao CP, Hou JQ, Ge JY, et al. 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.

    Article  CAS  PubMed  Google Scholar 

  11. Gonzalez-Rodriguez PJ, Tong W, Xue Q, Li Y, Hu S, Zhang LV. Fetal hypoxia results in programming of aberrant angiotensin II receptor expression patterns and kidney development. Int J Med Sci. 2013;10(5):532–538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Allam HI, Rahman TA. 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-Evans SC, Welham SJ, Jackson AA. Fetal exposure to a maternal low protein diet impairs nephrogenesis and promotes hypertension in the rat. Life Sci. 1999;64(11):965–974.

    Article  CAS  PubMed  Google Scholar 

  14. Lloyd LJ, Foster T, Rhodes P, Rhind SM, Gardner DS. 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.

    Article  CAS  PubMed  Google Scholar 

  15. Koseki C, Herzlinger D, Al-Awqati Q. Apoptosis in metanephric development. J Cell Biol. 1992;119(5):1327–1333.

    Article  CAS  PubMed  Google Scholar 

  16. Welham SJ, Wade A, Woolf AS. 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.

    Article  CAS  PubMed  Google Scholar 

  17. Dziarmaga A, Eccles M, Goodyer P. 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.

    Article  CAS  PubMed  Google Scholar 

  18. Narlis M, Grote D, Gaitan Y, Boualia SK, Bouchard M. Pax2 and Pax8 regulate branching morphogenesis and nephron differentiation in the developing kidney. J Am Soc Nephrol. 2007;18(4):1121–1129.

    Article  CAS  PubMed  Google Scholar 

  19. Thorburn A. Apoptosis and autophagy: regulatory connections between two supposedly different processes. Apoptosis. 2008;13(1):1–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Coles HS, Burne JF, Raff MC. Large-scale normal cell death in the developing rat kidney and its reduction by epidermal growth factor. Development. 1993;118(3):777–784.

    CAS  PubMed  Google Scholar 

  21. Sorenson CM. Life, death and kidneys: regulation of renal programmed cell death. Curr Opin Nephrol Hypertens. 1998;7(1):5–12.

    Article  CAS  PubMed  Google Scholar 

  22. Woolf AS, Welham SJ. Cell turnover in normal and abnormal kidney development. Nephrol Dial Transplant. 2002;17(suppl 9):2–4.

    Article  CAS  PubMed  Google Scholar 

  23. Pham TD, MacLennan NK, Chiu CT, Laksana GS, Hsu JL, Lane RH. Uteroplacental insufficiency increases apoptosis and alters p53 gene methylation in the full-term IUGR rat kidney. Am J Physiol. 2003;285:R962–R970.

    CAS  Google Scholar 

  24. He CC, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009;43:67–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shi LJ, Mao CP, Wu JW, Morrissey P, Lee JX, Xu ZC. 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.

    Article  CAS  PubMed  Google Scholar 

  26. Yang WL, Mao CP, Xia F, et al. Changed salt appetite and central angiotensin Il-induced cellular activation in rat offspring following hypoxia during fetal stages. Peptides. 2010;31(6):1177–1183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Murotsuki J, Challis JR, Han VK, Frahe LJ, Gagnon R. Chronic fetal placental embolization and hypoxemia cause hypertension and myocardial hypertrophy in fetal sheep. Am J Physiol. 1997;272(1 pt 2):R201–R207.

    CAS  PubMed  Google Scholar 

  28. Luzi G, Bori S, Iammarino G, et al. Functional aspects of the fetal urinary apparatus in relation to growth. Arch Ital Urol Androl. 1996;68(5 suppl):9–12.

    CAS  PubMed  Google Scholar 

  29. Vehaskari VM, Aviles DH, Manning J. Prenatal programming of adult hypertension in the rat. Kidney Int. 2001;59(1):238–245.

    Article  CAS  PubMed  Google Scholar 

  30. Welham SJ, Wade A, Woolf AS. Protein restriction in pregnancy is associated with increased apoptosis of mesenchymal cells at the start of rat metanephrogenesis. Kidney Int. 2002;61:1231–1242.

    Article  CAS  PubMed  Google Scholar 

  31. LeBrun DP, Warnke RA, Cleary ML. Expression of bcl-2 in fetal tissues suggests a role in morphogenesis. Am J Pathol. 1993;142(3):743–753.

    Google Scholar 

  32. Lee P, Sata M, Lefer DJ, Factor SM, Walsh K, Kitsis RN. 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.

    Article  CAS  PubMed  Google Scholar 

  33. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008;451(7182):1069–1075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rubinsztein DC. The roles of intracellular protein degradation pathways in neurodegeneration. Nature. 2006;443(7113):780–786.

    Article  CAS  PubMed  Google Scholar 

  35. Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140(3):313–326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ichimura Y, Kumanomidou T, Sou YS, et al. Structural basis for sorting mechanism of p62 in selective autophagy. J Biol Chem. 2008;283(33):22847–22857.

    Article  CAS  PubMed  Google Scholar 

  37. Yla-Anttila P, Vihinen H, Jokitalo E, Eskelinen EL. Monitoring autophagy by electron microscopy in Mammalian cells. Methods Enzymol. 2009;452:143–164.

    Article  PubMed  CAS  Google Scholar 

  38. Codogno P, Meijer AJ. Atg5: more than an autophagy factor. Nat Cell Biol. 2006;8(10):1045–1047.

    Article  CAS  PubMed  Google Scholar 

  39. Matsushita M, Suzuki NN, Obara K, Fujioka Y, Ohsumi Y, Inagaki F. Structure of Atg5•Atg16, a complex essential for autophagy. J Biol Chem. 2007;282(9):6763–6772.

    Article  CAS  PubMed  Google Scholar 

  40. Clark RS, Bayir H, Chu CT, Alber SM, Kochanek PM, Watkins SC. 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.

    Article  CAS  PubMed  Google Scholar 

  41. Maiuri MC, Le Toumelin G, Criollo A, et al. Functional and physical interaction between Bcl-XL and a BH3-like domain in Beclin-1. EMBO J. 2007;26(10):2527–2539.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Oberstein A, Jeffrey PD, Shi YG. 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.

    Article  CAS  PubMed  Google Scholar 

  43. Maiuri MC, Criollo A, Tasdemir E, et al. 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.

    Article  CAS  PubMed  Google Scholar 

  44. Zhang HF, Bosch-Marce M, Shimoda LA, et al. Mitochondrial autophagy is an HIF-1-dependent adaptive etabolic response to hypoxia. J Biol Chem. 2008;283(16):10892–10903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Noda T, Ohsumi Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem. 1998;273(7):3963–3966.

    Article  CAS  PubMed  Google Scholar 

  46. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124(3):471–484.

    Article  CAS  PubMed  Google Scholar 

  47. Codogno P, Meijer AJ. Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ. 2005;12 Suppl 2:1509–1518.

    Article  CAS  PubMed  Google Scholar 

  48. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18(16):1926–1945.

    Article  CAS  PubMed  Google Scholar 

  49. Gozuacik D, Bialik S, Raveh T, et al. DAP-kinase is a mediator of endoplasmic reticulum stress-induced caspase activation and autophagic cell death. Cell Death Differ. 2008;15(12):1875–1886.

    Article  CAS  PubMed  Google Scholar 

  50. Levine B, Yuan J. Autophagy in cell death: an innocent convict? J Clin Invest. 2005;115(10):2679–2688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 2007;8(9):741–752.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institute for Fetology, First Hospital of Soochow University, Suzhou, China

    Shuixiu Xia PhD, Juanxiu Lv PhD, Qinqin Gao PhD, Lingjun Li MS, Ningjing Chen MS, Xiaoguang Wei MS, Jianping Xiao PhD, Jie Chen PhD, Jianying Tao PhD, Miao Sun PhD, Caiping Mao PhD, Lubo Zhang PhD & Zhice Xu PhD

  2. Center for Perinatal Biology, Loma Linda University, Loma Linda, CA, USA

    Lubo Zhang PhD & Zhice Xu PhD

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  1. Shuixiu Xia PhD
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Correspondence to Zhice Xu PhD.

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Xia, S., Lv, J., Gao, Q. et al. Prenatal Exposure to Hypoxia Induced Beclin 1 Signaling-Mediated Renal Autophagy and Altered Renal Development in Rat Fetuses. Reprod. Sci. 22, 156–164 (2015). https://doi.org/10.1177/1933719114536474

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