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 α 3 or β 1 integrin, or the α 3 β 1 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 β 1 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.

The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier

“…The medical relevance of podocyte adhesion is underlined by the fact that podocyte detachment is a key factor for chronic kidney disease progression (32)(33)(34). Previous studies mainly focused on key components of the integrin adhesome, such as different integrin subunits or central signaling proteins such as ILK and TALIN (11,12,15). Despite those previous advances, there is still only limited knowledge about cell type-specific modulation of cell adhesion and contractility.…”

“…S5, S6, and S20). More recently, it was demonstrated that loss of TALIN (genetic deletion and experimental stress models), a well-established core focal adhesome component, results in a dramatic podocyte phenotype characterized by massive proteinuria, as well as consecutive development of glomerular sclerosis (15). Interestingly, TALINdeficient podocytes exhibited a mild adhesion and spreading defect, but a predominant misconfiguration of the actin cytoskeleton.…”

“…The clinical relevance of the adhesome for podocyte function was recently demonstrated by the identification of mutations in the Integrin alpha3 gene, causing glomerular and skin disease in affected patients (10). In addition, other focal adhesome components such as INTEGRIN-beta1 and INTEGRIN-LINKED KINASE (ILK), as well as other core focal adhesome components, were identified to be critical for podocyte maintenance (11)(12)(13)(14)(15).…”

Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

“…Alterations in these signaling pathways, frequently caused by genetic mutations within these networks that are responsible for biochemical dysfunctions in proteins and in their related signaling cascades, may progress to glomerular diseases (Wiggins, 2007;Mathieson, 2008). One of the key components of the podocyte signaling hub is nephrin, which appears to be controlled at multiple levels by the modulation of its phosphorylation state via Src family tyrosine kinases (Fyn, Yes, Src) and trafficking (Quack et al, 2006) or by a direct degradation process mediated by calpain (Peltier et al, 2006;Tian et al, 2014).…”

Essential Role of X-Box Binding Protein-1 during Endoplasmic Reticulum Stress in Podocytes

“…39 Glomeruli were harvested and enriched from mice kidney cortical tissue with 45% Percoll solution (GE Healthcare BioSciences, Uppsala, Sweden) as previously described. 40 The kidneys were harvested immediately and washed in ice-cold Krebs-Henseleit saline solution (119 mM NaCl, 4.7 mM KCl, 1.9 mM CaCl 2 , 1.2 mM L KH 2 PO 4 , 1.2 mM MgSO 4 , 7H 2 O, and 25 mM NaHCO 3 , pH, 7.4). The renal cortex segments were dissected away and finely minced into small pieces, then incubated with 1 mg/ml collagenase (Roche, Mannheim, Germany) at 37°C for 30 minutes.…”