Cerebral ischemia induces TRPC6 via HIF1α/ZEB2 axis in the glomerular podocytes and contributes to proteinuria

• Published in: Scientific reports 2019-11, Vol.9 (1), p.17897-13, Article 17897
• Main Authors: Nakuluri, Krishnamurthy, Nishad, Rajkishor, Mukhi, Dhanunjay, Kumar, Sireesh, Nakka, Venkata P., Kolligundla, Lakshmi P., Narne, Parimala, Natuva, Sai Sampath K., Phanithi, Prakash Babu, Pasupulati, Anil K.
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/51; 13/95; 14/19; 14/28; 38/77; 631/443/272/1684/1587/2101; 631/80/128/2031; Actin Cytoskeleton; Animals; Calcium; Calcium (intracellular); Calcium - metabolism; Calcium Channel Blockers - pharmacology; Calcium influx; Cell Line; Cerebral blood flow; Disease Models, Animal; Fibers; Focal adhesion kinase; Focal Adhesion Protein-Tyrosine Kinases - metabolism; Glomerulus; Homeobox; Humanities and Social Sciences; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Infarction, Middle Cerebral Artery - complications; Infarction, Middle Cerebral Artery - metabolism; Infarction, Middle Cerebral Artery - pathology; Ischemia; Kidney Glomerulus - cytology; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Male; multidisciplinary; Permeability - drug effects; Phosphorylation; Podocytes - cytology; Podocytes - metabolism; Proteinuria; Proteinuria - etiology; Rats; Rats, Sprague-Dawley; Science; Science (multidisciplinary); Structure-function relationships; Transient receptor potential proteins; TRPC Cation Channels - metabolism; Ultrafiltration; Zinc Finger E-box Binding Homeobox 2 - metabolism; Zinc finger proteins
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-52872-5

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.