Integrin a2-deficient mice provide insights into specific functions of collagen receptors in the kidney

Abstract

Background: Integrins are important cellular receptors for collagens. Within the glomerulus, podocytes regulate the integrity of the glomerular basement membrane (GBM) by sensing the presence of collagen and regulating collagen IV synthesis. The present study evaluates the role of integrin a2 (ITGA2) in cell-matrix interaction. Methods and Results: ITGA2-deficient mice had normal renal function but moderate proteinuria and enhanced glomerular and tubulointerstitial matrix deposition. Electron microscopy demonstrated irregular podocyte-matrix interaction, causing pathological protrusions towards the urinary (podocyte) side of the GBM. These characteristic subepithelial bulges mimic the renal phenotype of mice, which are deficient in another collagen receptor, discoidin domain receptor (DDR)1. Using immunogold staining, ITGA2 expression was found to localize to the basolateral site of the podocyte foot processes. ITGA2-deficient mice overexpressed transforming growth factor (TGF)b and connective tissue growth factor (CTGF) compared with wild-type mice. Using in situ hybridization, tubular cells were found to be the primary site of TGFb synthesis and podocytes the source of CTGF in ITGA2- deficient mice. Conclusion: These findings support our hypothesis that both these collagen receptors (ITGA2 and DDR1) play a similar role within the kidney. Further, cell-matrix interaction via collagen receptors seems to be crucial for maintenance of normal GBM architecture and function. Targeting collagen receptors such as ITGA2 might be a new form of treatment for progressive fibrotic diseases.