Abstract
Podocytes are a key component of the glomerular filtration barrier (GFB), which plays a critical role in ensuing ultra-filtrated urine. The integrity of the GFB is compromised during ischemic stroke and is manifested by proteinuria. The mechanism by which glomerular permselectivity is compromised during stroke remains enigmatic. Hypoxia is a determining factor in the pathology of ischemic stroke. We investigated the mechanism of ischemia-hypoxia-induced proteinuria in a middle cerebral artery occlusion (MCAO) stroke model. Ischemia-hypoxia resulted in the accumulation of HIF1α in the glomerular podocytes, which further resulted in the elevated expression of ZEB2. ZEB2, in turn, induced the expression of transient receptor potential cation channel, subfamily C, member 6 (TRPC6) that has increased selectivity for calcium. Elevated expression of TRPC6 elicited increased calcium influx and aberrant activation of focal adhesion kinase (FAK). FAK activation resulted in the stress fibers reorganization and foot process effacement. Our study suggests that ischemia-hypoxia induced HIF1α-ZEB2-TRPC6 axis in podocytes resulted in increased intracellular calcium levels and consequently altered podocyte integrity and permselectivity.