p21-activated kinases regulate actin remodeling in glomerular podocytes.

Abstract

The tyrosine phosphorylation of nephrin is reported to regulate podocyte morphology via the Nck adaptor proteins. The Pak family of kinases are regulators of the actin cytoskeleton and are recruited to the plasma membrane via Nck. Here, we investigated the role of Pak in podocyte morphology. Pak1/2 were expressed in cultured podocytes. In mouse podocytes, Pak2 was predominantly phosphorylated, concentrated at the tips of the cellular processes, and its expression and/or phosphorylation were further increased when differentiated. Overexpression of rat nephrin in podocytes increased Pak1/2 phosphorylation, which was abolished when the Nck binding sites were mutated. Furthermore, dominant-negative Nck constructs blocked the Pak1 phosphorylation induced by antibody-mediated cross linking of nephrin. Transient transfection of constitutively kinase-active Pak1 into differentiated mouse podocytes decreased stress fibers, increased cortical F-actin, and extended the cellular processes, whereas kinase-dead mutant, kinase inhibitory construct, and Pak2 knockdown by shRNA had the opposite effect. In a rat model of puromycin aminonucleoside nephrosis, Pak1/2 phosphorylation was decreased in glomeruli, concomitantly with a decrease of nephrin tyrosine phosphorylation. These results suggest that Pak contributes to remodeling of the actin cytoskeleton in podocytes. Disturbed nephrin-Nck-Pak interaction may contribute to abnormal morphology of podocytes and proteinuria.

• Authors: Jianxin Zhu, Ortal Attias, Lamine Aoudjit, Ruihua Jiang, Hiroshi Kawachi, Tomoko Takano
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 298 Issue 4 Pg. F951-61 (Apr 2010) ISSN: 1522-1466 [Electronic] United States
• PMID: 20071462 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Antibiotics, Antineoplastic
• Isoenzymes
• Membrane Proteins
• Plakins
• nephrin
• Puromycin Aminonucleoside
• p21-Activated Kinases

Topics

• Actins (physiology)
• Animals
• Antibiotics, Antineoplastic (adverse effects)
• Cell Line
• Gene Expression Regulation (physiology)
• Gene Expression Regulation, Enzymologic
• Humans
• Isoenzymes
• Kidney Glomerulus (cytology, metabolism)
• Membrane Proteins (genetics, metabolism)
• Mice
• Nephrosis (chemically induced, metabolism)
• Phosphorylation
• Plakins (physiology)
• Podocytes (cytology, metabolism)
• Puromycin Aminonucleoside (adverse effects)
• Rats
• p21-Activated Kinases (genetics, metabolism)