Zyxin deficiency aggravates podocyte injury in hypertensive nephropathy.

Podocyte injury and detachment are early cellular events in hypertensive nephropathy, yet their underlying mechanisms are not well clarified. Zyxin, a mechanotransducer located at focal adhesions, regulates actin cytoskeleton remodeling and exhibits diverse biological functions. However, its role in podocytes is poorly understood. In this study, we constructed a hypertensive nephropathy model in podocyte-specific zyxin knockout mice to explore the role of zyxin in hypertensive conditions. In vitro, mechanical stretch and Angiotensin II (AngII) were used to stimulate podocytes. Western blot, real-time PCR, and immunofluorescence were performed to underscore underlying mechanisms. We identified decreased zyxin levels in the glomeruli of a hypertensive nephropathy mouse model. Mechanical stretch and AngII altered zyxin expression and distribution in podocytes. Moreover, podocyte-specific zyxin knockout worsened hypertension-induced renal dysfunction, glomerulosclerosis, glomerular basement membrane thickening, foot process effacement, and podocyte loss. Zyxin knockdown disrupted the actin cytoskeleton, accompanied by reduced α-actinin-4 expression and changes in focal adhesion proteins, including vinculin and paxillin, which may contribute to altered podocyte motility and adhesion. These findings indicate that zyxin is involved in the regulation of podocyte cytoskeletal organization and cell behavior, likely through coordinated effects on multiple cytoskeletal and focal adhesion-related pathways rather than a single downstream mediator. In this context, zyxin may play a protective role in maintaining podocyte stability during hypertensive nephropathy.