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 beta 1-integrin in the entire renal CD causes defective CD morphogenesis resulting in kidney dysfunction. However, subsequent deletion of beta 1-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 beta 1integrin in CD cells, specifically in the PCs. We conditionally deleted beta 1-integrin in mouse CD PCs using a specific aquaporin-2 (AQP2) promoter Cre-LoxP system. The resulting mutant mice, beta-1(f/f)AQP2-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-beta (TGF-beta)-induced protein, fibronectin, and TGF-beta receptor-1 mRNAs and concomitantly increased phosphorylation of SMAD-2 that indicates the activation of the TGF-beta signaling pathway. Therefore, our data reveal that normal expression of beta 1-integrin in PCs is a critical determinant of CD structural and functional integrity and further support the previously reported critical role of beta 1-integrin in the development and/or maintenance of the CD structure and function.National Cancer Institute T32 Training Grant [5T32CA079443-15]; NephCure Foundation; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK-096015]; Gottschalk Research grant; Massachusetts General Hospital ECOR support; S& R Foundation Ryuji Ueno Award; Boston Area Diabetes and the Endocrinology Research Center (NIDDK Grant) [DK-57521]; Center for the Study of Inflammatory Bowel Disease (NICCK Grant) [DK-43351]SCI(E)ARTICLE4F1026-F103731