TY - JOUR
T1 - Hypoxia induces ZEB2 in podocytes
T2 - Implications in the pathogenesis of proteinuria
AU - Nakuluri, Krishnamurthy
AU - Mukhi, Dhanunjay
AU - Nishad, Rajkishor
AU - Saleem, Moin A.
AU - Mungamuri, Sathish Kumar
AU - Menon, Ram K.
AU - Pasupulati, Anil Kumar
N1 - © 2018 Wiley Periodicals, Inc.
PY - 2019/5
Y1 - 2019/5
N2 - 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.
AB - 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.
KW - HIF1α
KW - hypoxia
KW - podocyte
KW - proteinuria
KW - ZEB2.
UR - http://www.scopus.com/inward/record.url?scp=85053683762&partnerID=8YFLogxK
U2 - 10.1002/jcp.27387
DO - 10.1002/jcp.27387
M3 - Article (Academic Journal)
C2 - 30238984
VL - 234
SP - 6503
EP - 6518
JO - Journal of Cellular Physiology
JF - Journal of Cellular Physiology
SN - 0021-9541
IS - 5
ER -