Podocyte-associated talin1 is critical for glomerular filtration barrier maintenance

Xuefei Tian, Jin Ju Kim, Susan M. Monkley, Nanami Gotoh, Ramiro Nandez, Keita Soda, Kazunori Inoue, Daniel M. Balkin, Hossam Hassan, Sung Hyun Son, Yashang Lee, Gilbert Moeckel, David A. Calderwood, Lawrence B. Holzman, David R. Critchley, Roy Zent, Jochen Reiser, Shuta Ishibe

Research output: Contribution to journalArticlepeer-review

115 Scopus citations

Abstract

Podocytes are specialized actin-rich epithelial cells that line the kidney glomerular filtration barrier. The interface between the podocyte and the glomerular basement membrane requires integrins, and defects in either α3 or βl1 integrin, or the α3β1 ligand laminin result in nephrotic syndrome in murine models. The large cytoskeletal protein talin1 is not only pivotal for integrin activation, but also directly links integrins to the actin cytoskeleton. Here, we found that mice lacking talin1 specifically in podocytes display severe proteinuria, foot process effacement, and kidney failure. Loss of talin1 in podocytes caused only a modest reduction in β1 integrin activation, podocyte cell adhesion, and cell spreading; however, the actin cytoskeleton of podocytes was profoundly altered by the loss of talin1. Evaluation of murine models of glomerular injury and patients with nephrotic syndrome revealed that calpain-induced talin1 cleavage in podocytes might promote pathogenesis of nephrotic syndrome. Furthermore, pharmacologic inhibition of calpain activity following glomerular injury substantially reduced talin1 cleavage, albuminuria, and foot process effacement. Collectively, these findings indicate that podocyte talin1 is critical for maintaining the integrity of the glomerular filtration barrier and provide insight into the pathogenesis of nephrotic syndrome.

Original languageEnglish (US)
Pages (from-to)1098-1113
Number of pages16
JournalJournal of Clinical Investigation
Volume124
Issue number3
DOIs
StatePublished - Mar 3 2014
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine

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