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. 2015 Feb;22(2):156-64.
doi: 10.1177/1933719114536474. Epub 2014 May 28.

Prenatal exposure to hypoxia induced Beclin 1 signaling-mediated renal autophagy and altered renal development in rat fetuses

Shuixiu Xia  1 , Juanxiu Lv  1 , Qinqin Gao  1 , Lingjun Li  1 , Ningjing Chen  1 , Xiaoguang Wei  1 , Jianping Xiao  1 , Jie Chen  1 , Jianying Tao  1 , Miao Sun  1 , Caiping Mao  1 , Lubo Zhang  2 , Zhice Xu  3
Affiliations

Prenatal exposure to hypoxia induced Beclin 1 signaling-mediated renal autophagy and altered renal development in rat fetuses

Shuixiu Xia et al. Reprod Sci. 2015 Feb.

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.

Keywords: autophagy; hypoxia; kidney; rat fetus.

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Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Fetal kidney, body weight, and ratio of kidney–body weight at gestation day (GD) 21 following exposure to hypoxia. *, P < .05.
Figure 2.
Figure 2.
The fetal renal cortex showed immature glomeruli (nonvascularized) in the cortical periphery and mature (vascularized) glomeruli mostly in the deep cortex in all groups (A and C: control; B and D: hypoxia. A and B: ×10; C and D: ×40). The interstitium in the hypoxia group was much wider than that of the control, and cells in the interstitium was obviously increased (A and B). The Bowman space was enlarged, while the size of the solid core of the glomeruli was reduced, and the number of parenchymal cells of partial glomeruli was decreased in the fetuses exposed to hypoxia (C and D). Solid arrow: immature glomeruli; open arrow: mature glomeruli; dotted line arrow: the Bowman space. IN indicates interstitium.
Figure 3.
Figure 3.
Fetal renal soluble FAS (sFAS) and APG5L. Control (n = 15) and hypoxia (n = 16). *, P < .05.
Figure 4.
Figure 4.
The effect of chronic hypoxia on signaling proteins of autophagy and apoptosis in the fetal kidney. *, P < .05.
Figure 5.
Figure 5.
The number of apoptosis cells apparently increased with the enhanced number of positive 2′-deoxyuridine 5′-triphosphate nick end-labeling (TUNEL) staining (white dots, ×20) in the fetal kidneys following hypoxia. A, Control and (B) hypoxia.
Figure 6.
Figure 6.
High magnification of transmitted electron microscopy (TEM) showing structures of autophagosomes (AP), autolysosomes (AL), and mitochondria (M) in the fetal kidney. A and B, Glomerulus (scale bars: 2 μm); C and D, podocyte (scale bars: 0.5 μm). A and C, Control; B and D, hypoxia. Black arrow: podocyte foot process; arrow with white surrounding: autolysosomes (AL). PC indicates podocyte.
Figure 7.
Figure 7.
Fetal renal autophagic protein (LC3) following exposure to hypoxia. *, P < .05.
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