Podocyte-specific loss of Cdc42 leads to congenital nephropathy

Rizaldy P. Scott, Steve P. Hawley, Julie Ruston, Jianmei Du, Cord Brakebusch, Nina Jones, Tony Pawson*

*Corresponding author for this work

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

Rho family GTPases are molecular switches best known for their pivotal role in dynamic regulation of the actin cytoskeleton. The prototypic members of this family are Cdc42, Rac1, and RhoA; these GTPases contribute to the breakdown of glomerular filtration and the resultant proteinuria, but their functions in normal podocyte physiology remain poorly understood. Here, mice lacking Cdc42 in podocytes developed congenital nephropathy and died as a result of renal failure within 2 weeks after birth. In contrast, mice lacking Rac1 or RhoA in podocytes were overtly normal and lived to adulthood. Kidneys from Cdc42-mutant mice exhibited protein-filled microcysts with hallmarks of collapsing glomerulopathy, as well as extensive effacement of podocyte foot processes with abnormal junctional complexes. Furthermore, we observed aberrant expression of several podocyte markers and cell polarity proteins in the absence of Cdc42, indicating a disruption of the slit diaphragm. Kidneys from Rac1- and RhoA-mutant mice, however, had normal glomerular morphology and intact foot processes. A nephrin clustering assay suggested that Cdc42 deficiency, but not Rac1 or RhoA deficiency, impairs the polymerization of actin at sites of nephrin aggregates. Taken together, these data highlight the physiological importance of Cdc42, but not Rac1 or RhoA, in establishing podocyte architecture and glomerular function.

Original languageEnglish (US)
Pages (from-to)1149-1154
Number of pages6
JournalJournal of the American Society of Nephrology
Volume23
Issue number7
DOIs
StatePublished - Jul 1 2012

ASJC Scopus subject areas

  • Nephrology

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    Scott, R. P., Hawley, S. P., Ruston, J., Du, J., Brakebusch, C., Jones, N., & Pawson, T. (2012). Podocyte-specific loss of Cdc42 leads to congenital nephropathy. Journal of the American Society of Nephrology, 23(7), 1149-1154. https://doi.org/10.1681/ASN.2011121206