Abstract
Podocytes are specialized cells of the glomerulus and key component of the glomerular filtration apparatus (GFA). GFA regulates the permselectivity and ultrafiltration of blood. The mechanism by which the integrity of the GFA is compromised and manifest in proteinuria during ischemic stroke remains enigmatic. We investigated the mechanism of ischemic hypoxia-induced proteinuria in a middle cerebral artery occlusion (MCAO) model. Ischemic hypoxia resulted in the accumulation of HIF1α in the podocytes that resulted in the increased expression of ZEB2 (Zinc finger E-box-binding homeobox 2). 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 HIF1α/ZEB2 axis during ischemic-hypoxia raises intracellular calcium levels via TRPC6 and consequently altered podocyte structure and function thus contributes to proteinuria.
Highlights
Extreme physiological and pathological conditions impose challenges on human physiology
The ischemic stroke resulted in systemic hypoxia and proteinuria
Ischemic region of the brain showed white color when stained with tetrazolium chloride (TTC) indicating the infarct lesions (Fig. 1A). 24 h following the Middle cerebral artery occlusion (MCAO) surgery in rats, we measured the urine albumin to creatinine ratio (ACR) to evaluate the effect of ischemic stroke injury on renal function
Summary
Extreme physiological and pathological conditions impose challenges on human physiology. Limitations in oxygen supply impose kidneys to undergo hypoxia-induced maladaptation, which likely reflects in the pathophysiology of acute kidney injury and proteinuria[6,7,8,9,10,11,12]. Three layers of GFA are podocytes, glomerular basement membrane (GBM), and perforated endothelium[13] Clinical conditions such as stroke and sleep apnea are associated with proteinuria and are presented with reduced renal perfusion and moderate to severe hypoxia[12,14]. We found that ischemic stroke and the resultant hypoxic injury manifested in the elevated expression of HIF1α in various organs including kidney. We observed elevated expression of ZEB2 and TRPC6 in glomerular podocytes from ischemic stroke rats. Overactivity of the HIF1α/ ZEB2 axis and TRPC6 could be a mechanism by which systemic hypoxia manifests in podocyte injury and proteinuria
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call