title: 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
authors: X
authors: Tian
authors: Jin Ju
authors: JJ
authors: Kim
authors: Susan M
authors: SM
authors: Monkley
authors: Nanami
authors: N
authors: Gotoh
authors: Ramiro
authors: R
authors: Nandez
authors: Keita
authors: K
authors: Soda
authors: Kazunori
authors: K
authors: Inoue
authors: Daniel M
authors: DM
authors: Balkin
authors: Hossam
authors: H
authors: Hassan
authors: Sung Hyun
authors: SH
authors: Son
authors: Yashang
authors: Y
authors: Lee
authors: Gilbert
authors: G
authors: Moeckel
authors: David A
authors: DA
authors: Calderwood
authors: Lawrence B
authors: LB
authors: Holzman
authors: David R
authors: DR
authors: Critchley
authors: Roy
authors: R
authors: Zent
authors: Jochen
authors: J
authors: Reiser
authors: Shuta
authors: S
authors: Ishibe
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D002154:Calpain / Q000378:metabolism; D002448:Cell Adhesion; D002478:Cells, Cultured; D022001:Focal Adhesions / Q000378:metabolism; D060730:Glomerular Filtration Barrier / Q000473:pathology*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009404:Nephrotic Syndrome / Q000378:metabolism* / Q000473:pathology; D050199:Podocytes / Q000378:metabolism*; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D051437:Renal Insufficiency / Q000235:genetics / Q000378:metabolism; D016608:Talin / Q000502:physiology*
chemical_list: D019012:Integrin beta1; D016608:Talin; C496077:Tln1 protein, mouse; D002154:Calpain