Hypoxia induces ZEB2 in podocytes: Implications in the pathogenesis of proteinuria

Abstract

The glomerular filtration barrier (GFB) plays a critical role in ensuing protein free urine. The integrity of the GFB is compromised during hypoxia that prevails during extreme physiological conditions. However, the mechanism by which glomerular permselectivity is compromised during hypoxia remains enigmatic. Rats exposed to hypoxia showed a decreased glomerular filtration rate, podocyte foot-processes effacement, and proteinuria. Accumulation of hypoxia-inducible factor-1α (HIF1α) in podocytes resulted in elevated expression of zinc finger E-box binding homeobox 2 (ZEB2) and decreased expression of E-and P-cadherin. We also demonstrated that HIF1α binds to hypoxia response element localized in the ZEB2 promoter.Furthermore, HIF1α also induced the expression of ZEB2-natural antisense transcript, which is known to increase the efficiency of ZEB2 translation. Ectopic expression of ZEB2 induced loss of E-and P-cadherin and is associated with enhanced motility of podocytes during hypoxic conditions. ZEB2 knockdown abrogated hypoxia-induced decrease in podocyte permselectivity. This study suggests that hypoxia leads to activation of HIF1α-ZEB2 axis, resulting in podocyte injury and poor renal outcome. K E Y W O R D SHIF1α, hypoxia, podocyte, proteinuria, ZEB2.

Cerebral ischemia induces TRPC6 via HIF1α/ZEB2 axis in the glomerular podocytes and contributes to proteinuria

“…ZEB2 expression is concomitant with HIF1α accumulation in podocytes exposed to hypoxia 22 . ZEB2, a zinc-finger transcription factor regulates the expression of several proteins representing various cellular processes including cell adhesion and epithelial-mesenchymal transition (EMT).…”

“…Earlier studies revealed that accumulation of HIF1α in podocytes increased podocyte permeability to albumin and blunting the expression of ZEB2 diminished the susceptibility podocyte monolayer to hypoxia-driven elevated albumin influx 22 . This data strongly suggest that ZEB2 is necessary to elicit HIF1α’s action on podocyte permeability.…”

“…E-cadherin is a well-known target for transcriptional suppression by ZEB2. Reduced E-cadherin expression is implicated with the transition of podocytes from epithelial to mesenchymal phenotype compromising their ability to provide epithelial coverage to glomerular capillaries 22,23 . However, in this study, we found that ZEB2 induces TRPC6 expression in podocytes.…”

“…Urine samples from rats were subjected to 10% SDS-PAGE gel and processed for silver staining as described earlier 22 . Urinary albumin (#11573) and creatinine (#11502) were measured using commercially available kits (Biosystems, Barcelona, Spain).…”

“…The glomeruli from the kidneys were isolated by a series of stainless sieves as described earlier 22 . Primary podocytes from rat kidney were isolated as reported earlier 61 .…”