Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | F1026-F1037 |
| Journal | American Journal of Physiology - Renal Physiology |
| Volume | 313 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Oct 9 2017 |
| Externally published | Yes |
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Keywords
- Aquaporin-2
- Collecting ducts
- Renal fibrosis
- TGF-β
- β1-integrins
ASJC Scopus subject areas
- Physiology
- Urology
Cite this
Deletion of β1-integrin in collecting duct principal cells leads to tubular injury and renal medullary fibrosis. / Mamuya, Fahmy A.; Xie, Dongping; Lei, Lei; Huang, Ming; Tsuji, Kenji; Capen, Diane E.; Yang, Baoxue; Weissleder, Ralph; Păunescu, Teodor G.; Jenny Lu, Hua A.
In: American Journal of Physiology - Renal Physiology, Vol. 313, No. 4, 09.10.2017, p. F1026-F1037.Research output: Contribution to journal › Article
}
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.
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
UR - http://www.scopus.com/inward/record.url?scp=85031299331&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85031299331&partnerID=8YFLogxK
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 -