Podocyte-associated talin1 is critical for glomerular filtration barrier maintenance.

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 β1 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.

• Authors: 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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 124 Issue 3 Pg. 1098-113 (Mar 2014) ISSN: 1558-8238 [Electronic] United States
• PMID: 24531545 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Integrin beta1
• Talin
• Tln1 protein, mouse
• Calpain

Topics

• Actin Cytoskeleton (metabolism)
• Animals
• Calpain (metabolism)
• Cell Adhesion
• Cells, Cultured
• Focal Adhesions (metabolism)
• Glomerular Filtration Barrier (pathology)
• Humans
• Integrin beta1 (metabolism)
• Mice
• Mice, Knockout
• Nephrotic Syndrome (metabolism, pathology)
• Podocytes (metabolism)
• Proteinuria (genetics, metabolism)
• Proteolysis
• Renal Insufficiency (genetics, metabolism)
• Talin (physiology)