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Deletion of β1-integrin in collecting duct principal cells leads to tubular injury and renal medullary fibrosis.
- Source :
-
American journal of physiology. Renal physiology [Am J Physiol Renal Physiol] 2017 Oct 01; Vol. 313 (4), pp. F1026-F1037. Date of Electronic Publication: 2017 Jul 12. - Publication Year :
- 2017
-
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-1 <superscript>f/f</superscript> 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-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.<br /> (Copyright © 2017 the American Physiological Society.)
- Subjects :
- Age Factors
Animals
Apoptosis
Aquaporin 2 genetics
Cell Proliferation
Extracellular Matrix ultrastructure
Failure to Thrive genetics
Failure to Thrive metabolism
Failure to Thrive pathology
Fibrosis
Genetic Predisposition to Disease
Integrases genetics
Integrin beta1 genetics
Kidney Medulla ultrastructure
Kidney Tubules, Collecting ultrastructure
Mice, Knockout
Phenotype
Phosphorylation
Polyuria genetics
Polyuria pathology
Promoter Regions, Genetic
Protein Serine-Threonine Kinases genetics
Protein Serine-Threonine Kinases metabolism
Receptor, Transforming Growth Factor-beta Type I
Receptors, Transforming Growth Factor beta genetics
Receptors, Transforming Growth Factor beta metabolism
Renal Insufficiency genetics
Renal Insufficiency pathology
Signal Transduction
Smad2 Protein metabolism
Transforming Growth Factor beta metabolism
Extracellular Matrix metabolism
Gene Deletion
Integrin beta1 metabolism
Kidney Medulla metabolism
Kidney Tubules, Collecting metabolism
Polyuria metabolism
Renal Insufficiency metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1466
- Volume :
- 313
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Renal physiology
- Publication Type :
- Academic Journal
- Accession number :
- 28701310
- Full Text :
- https://doi.org/10.1152/ajprenal.00038.2017