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

• Published in: Journal of cellular physiology 2019-05, Vol.234 (5), p.6503-6518
• Main Authors: Nakuluri, Krishnamurthy, Mukhi, Dhanunjay, Nishad, Rajkishor, Saleem, Moin A., Mungamuri, Sathish Kumar, Menon, Ram K., Pasupulati, Anil Kumar
• Format: Article
• Language: English
• Subjects: Animals; Antisense RNA; Ectopic expression; Glomerular filtration rate; HIF1α; Homeobox; Hypoxia; Hypoxia - metabolism; Hypoxia - physiopathology; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Pathogenesis; podocyte; Podocytes - metabolism; Podocytes - pathology; Proteins; Proteinuria; Proteinuria - metabolism; Proteinuria - physiopathology; Rats; Rats, Wistar; Transcription; Urine; ZEB2; Zinc Finger E-box Binding Homeobox 2 - metabolism; Zinc finger proteins
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.27387

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. Hypoxia induces hypoxia‐inducible factor‐1α (HIF1α) and zinc finger E‐box binding homeobox 2 (ZEB2) in podocytes. HIF1α induces the expression of ZEB2 in podocytes. ZEB2 overexpression ensures podocyte foot‐processes effacement and proteinuria.