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bioRxiv · 10.1101/538959

Cerebral Ischemic-Hypoxia Induces TRPC6 in the Glomerular Podocytes: A Novel Role for HIF1α-ZEB2 Axis in the Pathogenesis of Stroke-induced Proteinuria

Nakuluri, K.·Nishad, R.·Mukhi, D.·Teertam, S. K.·Nakka, V. P.·Narne, P.·Natuva, S. S. K.·Phanithi, P. B.·Pasupulati, A. K.
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Abstract

Glomerular filtration apparatus (GFA) regulates the glomerular permselectivity and ultrafiltration of urine. Podocytes are specialized cells and a key component of the GFA. The mechanism by which the integrity of the GFA is compromised and manifest in proteinuria during ischemic stroke remains enigmatic. Hypoxia is a determining factor in the pathophysiology of ischemia. We investigated the mechanism of ischemic-hypoxia induced proteinuria in a middle cerebral artery occlusion (MCAO) model. Ischemic hypoxia resulted in the accumulation of HIF1 in the glomerular podocytes that resulted in the increased expression of ZEB2. ZEB2, in turn, induced TRPC6 (transient receptor potential cation channel, subfamily C, member 6), which has increased selectivity for calcium. Elevated expression of TRPC6 elicited increased calcium influx and aberrant activation of focal adhesion kinase (FAK) in podocytes. FAK activation resulted in the stress fibers reorganization and podocyte foot process effacement. Our study suggests overactive HIF1/ZEB2 axis during ischemic-hypoxia induces intracellular calcium levels via TRPC6 and consequently altered podocyte integrity and permselectivity.

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Nakuluri, K., Nishad, R., Mukhi, D., Teertam, S. K., Nakka, V. P., Narne, P., Natuva, S. S. K., Phanithi, P. B., Pasupulati, A. K.. 2019-02-03. Cerebral Ischemic-Hypoxia Induces TRPC6 in the Glomerular Podocytes: A Novel Role for HIF1α-ZEB2 Axis in the Pathogenesis of Stroke-induced Proteinuria. https://doi.org/10.1101/538959

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