Hypoxia‐inducible factor‐1α attenuates renal podocyte injury in male rats in a simulated high‐altitude environment by upregulating Krüppel‐like factor 4 expression

Abstract Previous studies have shown that podocyte injury is involved in the development of proteinuria in rats under hypobaric hypoxia conditions. Prolyl hydroxylase inhibitors (PHIs) may reduce proteinuria. This study aimed to further investigate whether the protective effects of hypoxia‐inducible factor 1α (HIF1α) on podocyte injury induced by hypobaric hypoxia are related to Krüppel‐like factor 4 (KLF4). Rats were housed in a low‐pressure oxygen chamber to simulate a high‐altitude environment (5000 m), and a PHI was intraperitoneally injected. Urinary protein electrophoresis was performed and the morphology of the podocytes was observed by electron microscopy. Rat podocytes were cultured under 1% O 2 , and siRNA was used to interfere with KLF4 expression. The protein expression levels of HIF1α, KLF4, CD2‐associated protein (CD2AP) and nephrin were determined by western blotting. Compared with those in the experimental group, the rats in the intervention group on day 14 had lower urinary protein levels, increased protein expression levels of CD2AP and nephrin, and reduced podocyte injury. The results of in vitro experiments showed that the protein expression levels of KLF4, CD2AP and nephrin were greater in the PHI intervention group and lower in the HIF1α inhibitors group than in the low‐oxygen group. The protein expression of CD2AP and nephrin in the siKLF4‐transfected podocytes treated with PHI and HIF1α inhibitors did not differ significantly from that in the low‐oxygen group. HIF1α may be involved in reducing progressive high‐altitude proteinuria by regulating KLF4 expression and contributing to the repair of podocyte injury induced by hypobaric hypoxia.