Genetic ablation of SLK exacerbates glomerular injury in adriamycin nephrosis in mice

Abstract

The Ste20-like kinase SLK is critical for embryonic development, and may play an important role in wound healing, muscle homeostasis, cell migration and tumor growth. Mice with podocyte-specific deletion of SLK show albuminuria, and damage to podocytes, as they age. The present study addresses the role of SLK in glomerular injury. We induced adriamycin nephrosis in 3-4 month control and podocyte SLK knockout (KO) mice. Compared with control, SLK deletion exacerbated albuminuria and loss of podocytes, synaptopodin and podocalyxin. Glomeruli of adriamycin-treated SLK KO mice showed diffuse increases in matrix and sclerosis, as well as collapse of the actin cytoskeleton. SLK can phosphorylate ezrin. The complex of phospho-ezrin, NHERF2 and podocalyxin in the apical domain of the podocyte is a key determinant of normal podocyte architecture. Deletion of SLK reduced glomerular ezrin and ezrin phosphorylation in adriamycin nephrosis. Also, deletion of SLK reduced the colocalization of ezrin and podocalyxin in the glomerulus. Cultured glomerular epithelial cells with KO of SLK showed reduced ezrin phosphorylation and podocalyxin expression, as well as reduced F-actin. Thus, SLK deletion leads to podocyte injury as mice age, and exacerbates injury in adriamycin nephrosis. The mechanism may at least in part involve ezrin phosphorylation, as well as disruption of the cytoskeleton and podocyte apical membrane structure.