Journal article
Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho
Kidney international, Vol.91(4), pp.830-841
04/2017
DOI: 10.1016/j.kint.2016.09.039
PMCID: PMC5357448
PMID: 27979597
Abstract
Fibrosis is an exaggerated form of tissue repair that occurs with serious damage or repetitive injury and ultimately leads to organ failure due to the excessive scarring. Increased calcium ion entry through the TRPC6 channel has been associated with the pathogenesis of heart and glomerular diseases, but its role in renal interstitial fibrosis is unknown. We studied this by deletion of Trpc6 in mice and found it decreased unilateral ureteral obstruction-induced interstitial fibrosis and blunted increased mRNA expression of fibrosis-related genes in the ureteral obstructed kidney relative to that in the kidney of wild-type mice. Administration of BTP2, a pyrazol derivative known to inhibit function of several TRPC channels, also ameliorated obstruction-induced renal fibrosis and gene expression in wild-type mice. BTP2 inhibited carbachol-activated TRPC3 and TRPC6 channel activities in HEK293 cells. Ureteral obstruction caused over a 10-fold increase in mRNA expression for TRPC3 as well as TRPC6 in the kidneys of obstructed relative to the sham-operated mice. The magnitude of protection against obstruction-induced fibrosis in Trpc3 and Trpc6 double knockout mice was not different from that in Trpc6 knockout mice. Klotho, a membrane and soluble protein predominantly produced in the kidney, is known to confer protection against renal fibrosis. Administration of soluble klotho significantly reduced obstruction-induced renal fibrosis in wild-type mice, but not in Trpc6 knockout mice, indicating that klotho and TRPC6 inhibition act in the same pathway to protect against obstruction-induced renal fibrosis. Thus klotho and TRPC6 may be pharmacologic targets for treating renal fibrosis.
Details
- Title: Subtitle
- Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho
- Creators
- Yueh-Lin Wu - Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USAJian Xie - Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USASung-Wan An - Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USANoelynn Oliver - CardioMetabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USANestor X Barrezueta - CardioMetabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USAMei-Hsiang Lin - School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, TaiwanLutz Birnbaumer - Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USAChou-Long Huang - Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Resource Type
- Journal article
- Publication Details
- Kidney international, Vol.91(4), pp.830-841
- DOI
- 10.1016/j.kint.2016.09.039
- PMID
- 27979597
- PMCID
- PMC5357448
- NLM abbreviation
- Kidney Int
- ISSN
- 0085-2538
- eISSN
- 1523-1755
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 04/2017
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984094332202771
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