Vasohibin-1 has a-tubulin detyrosinating activity in glomerular podocytes

Podocytes are highly specialized epithelial cells in glomeruli, with a complex morphology composed of a cell body, primary processes, and foot processes, which maintain barrier function in glomerular filtration. The microtubule-based cytoskeleton is necessary for podocyte morphology. Microtubule structure and function can be affected by post-translational modification of tubulin, including detyrosination. Recent studies have shown that vasohibin-1 (VASH1), an antiangiogenic factor, has tubulin carboxypeptidase activity that causes detyrosination of a-tubulin. We aimed to examine the role of VASH1 in regulating atubulin detyrosination in podocytes and the potential involvement of VASH1 deficiency in renal morphology. In normal mouse kidneys, detyrosinated a-tubulin was mainly identified in glomeruli, especially in podocytes; meanwhile, in cultured immortalized podocytes, a-tubulin detyrosination was promoted with cell differentiation. Notably, a-tubulin detyrosination in glomeruli was diminished in Vash1 homozygous knockout (Vash1-/-) mice, and knockdown of VASH1 in cultured podocytes prevented a-tubulin detyrosination. Although VASH1 deficiency-induced downregulation of detyrosination caused no remarkable glomerular lesions, urinary albuminuria excretion and glomerular volume were significantly higher in Vash1-/- mice than in wild-type mice. Furthermore, decreased glomerular nephrin expression and narrower slit diaphragms width were observed in Vash1-/- mice. Taken together, we demonstrated that a-tubulin detyrosination in podocytes was mainly regulated by VASH1 and that VASH1 deficiency-mediated decreases in a-tubulin detyrosination led to minor alterations in podocyte morphology and predisposition to albuminuria. VASH1 expression and a-tubulin detyrosination may be novel targets for maintaining glomerular filtration barrier integrity. (c) 2022 Elsevier Inc. All rights reserved.