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
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
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Research Article

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

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Figure 1

Generation of podocyte-specific Tln1-KO mice.

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Generation of podocyte-specific Tln1-KO mice. (A) Immunogold transmiss...
(A) Immunogold transmission EM staining demonstrates talin1 (arrowheads) localizes to the base of the foot process (fp) and adjacent to the slit diaphragm (SD) (arrows) of podocytes from WT mouse kidneys. Scale bars: 100 nm. (B) Schematic demonstrating breeding of the Podocin-Cre mice with Tln1fl/fl mice to generate podocyte-specific Tln1-KO mice (Pod-Tln1–KO). Forward and reverse primers are denoted as a and b, respectively, for Cre and Tln1. (C) Identification of Tln1 and Podocin-Cre by tail genotyping (age P7). (D and E) Talin1 expression in purified control (Ctrl) podocytes and lack of talin1 expression in podocytes harvested from Pod-Tln1–KO mice (age P7), as detected by Western blotting. (D) and immunofluorescence (E). Note that Ctrl podocytes express both talin1 and talin2. Podocytes were plated on collagen type I–coated glass coverslips and stained for WT1 (red) and for talin1 using an isoform-specific talin1 monoclonal Ab. Scale bars: 10 μm. (F) Double-immunofluorescence detection of nephrin (red) and talin1 (green) on kidney sections of the indicated genotypes (age P14). Scale bars: 10 μm (upper panels) 2 μm (lower panels).