Deletion of {beta}1-integrin in collecting duct principal cells leads to tubular injury and renal medullary fibrosis

The renal collecting duct (CD) contains two major cell types, intercalated (ICs) and principal cells (PCs). A previous report showed that deletion of β1-integrin in the entire renal CD causes defective CD morphogenesis resulting in kidney dysfunction. However, subsequent deletion of β1-integrin specifically in ICs and PCs, respectively, did not cause any morphological defects in the CDs. The discrepancy between these studies prompts us to reinvestigate the role of β1-integrin in CD cells, specifically in the PCs. We conditionally deleted β1-integrin in mouse CD PCs using a specific aquaporin-2 (AQP2) promoter Cre-LoxP system. The resulting mutant mice, β-1f/fAQP2-Cre+, had lower body weight, failed to thrive, and died around 8–12 wk. Their CD tubules were dilated, and some of them contained cellular debris. Increased apoptosis and proliferation of PCs were observed in the dilated CDs. Trichrome staining and electron microscopy revealed the presence of peritubular and interstitial fibrosis that is associated with increased production of extracellular matrix proteins including collagen type IV and fibronectin, as detected by immunoblotting. Further analysis revealed a significantly increased expression of transforming growth factor-β (TGF-β)-induced protein, fibronectin, and TGF-β receptor-1 mRNAs and concomitantly increased phosphorylation of SMAD-2 that indicates the activation of the TGF-β signaling pathway. Therefore, our d...

Source: AJP: Renal Physiology - October 9, 2017 Category: Urology & Nephrology Authors: Mamuya, F. A., Xie, D., Lei, L., Huang, M., Tsuji, K., Capen, D. E., Yang, B., Weissleder, R., Paunescu, T. G., Lu, H. A. J. Tags: RESEARCH ARTICLE Source Type: research