TY - JOUR
T1 - Deletion of β1-integrin in collecting duct principal cells leads to tubular injury and renal medullary fibrosis
AU - Mamuya, Fahmy A.
AU - Xie, Dongping
AU - Lei, Lei
AU - Huang, Ming
AU - Tsuji, Kenji
AU - Capen, Diane E.
AU - Yang, Baoxue
AU - Weissleder, Ralph
AU - Păunescu, Teodor G.
AU - Jenny Lu, Hua A.
N1 - Funding Information:
F. A. Mamuya is supported by National Cancer Institute T32 Training Grant 5T32CA079443-15. This work was supported by the NephCure Foundation, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant DK-096015, a Gottschalk Research grant, Massachusetts General Hospital ECOR support, and the S&R Foundation Ryuji Ueno Award (to H. A. Lu). The Microscopy Core facility of the Program in Membrane Biology receives additional support from the Boston Area Diabetes and the Endocrinology Research Center (NIDDK Grant DK-57521) and the Center for the Study of Inflammatory Bowel Disease (NICCK Grant DK-43351).
Publisher Copyright:
© 2017 the American Physiological Society.
PY - 2017/10/9
Y1 - 2017/10/9
N2 - 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 data reveal that normal expression of β1-integrin in PCs is a critical determinant of CD structural and functional integrity and further support the previously reported critical role of β1-integrin in the development and/or maintenance of the CD structure and function.
AB - 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 data reveal that normal expression of β1-integrin in PCs is a critical determinant of CD structural and functional integrity and further support the previously reported critical role of β1-integrin in the development and/or maintenance of the CD structure and function.
KW - Aquaporin-2
KW - Collecting ducts
KW - Renal fibrosis
KW - TGF-β
KW - β1-integrins
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U2 - 10.1152/ajprenal.00038.2017
DO - 10.1152/ajprenal.00038.2017
M3 - Article
C2 - 28701310
AN - SCOPUS:85031299331
VL - 313
SP - F1026-F1037
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
SN - 0363-6127
IS - 4
ER -