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Store-Operated Ca^(2+) Channels in Mesangial Cells Inhibit Matrix Protein Expression

Wu, Peiwen and Wang, Yanxia and Davis, Mark E. and Zuckerman, Jonathan E. and Chaudhari, Sarika and Begg, Malcolm and Ma, Rong (2015) Store-Operated Ca^(2+) Channels in Mesangial Cells Inhibit Matrix Protein Expression. Journal of the American Society of Nephrology, 26 (11). pp. 2691-2702. ISSN 1046-6673. PMCID PMC4625675. doi:10.1681/ASN.2014090853.

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Accumulation of extracellular matrix derived from glomerular mesangial cells is an early feature of diabetic nephropathy. Ca^(2+) signals mediated by store–operated Ca^(2+) channels regulate protein production in a variety of cell types. The aim of this study was to determine the effect of store–operated Ca^(2+) channels in mesangial cells on extracellular matrix protein expression. In cultured human mesangial cells, activation of store–operated Ca^(2+) channels by thapsigargin significantly decreased fibronectin protein expression and collagen IV mRNA expression in a dose-dependent manner. Conversely, inhibition of the channels by 2-aminoethyl diphenylborinate significantly increased the expression of fibronectin and collagen IV. Similarly, overexpression of stromal interacting molecule 1 reduced, but knockdown of calcium release–activated calcium channel protein 1 (Orai1) increased fibronectin protein expression. Furthermore, 2-aminoethyl diphenylborinate significantly augmented angiotensin II–induced fibronectin protein expression, whereas thapsigargin abrogated high glucose– and TGF-β1–stimulated matrix protein expression. In vivo knockdown of Orai1 in mesangial cells of mice using a targeted nanoparticle siRNA delivery system resulted in increased expression of glomerular fibronectin and collagen IV, and mice showed significant mesangial expansion compared with controls. Similarly, in vivo knockdown of stromal interacting molecule 1 in mesangial cells by recombinant adeno–associated virus–encoded shRNA markedly increased collagen IV protein expression in renal cortex and caused mesangial expansion in rats. These results suggest that store–operated Ca^(2+) channels in mesangial cells negatively regulate extracellular matrix protein expression in the kidney, which may serve as an endogenous renoprotective mechanism in diabetes.

Item Type:Article
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Davis, Mark E.0000-0001-8294-1477
Additional Information:© 2015 by the American Society of Nephrology. Received for publication September 3, 2014. Accepted for publication December 22, 2014. We thank GlaxoSmithKline for providing GSK-7975A compound and Dr. Tobias Meyer at Stanford University School of Medicine for providing YFP-STIM expression plasmid (pDS_XB_YFP-STIM1-II). The work was supported by National Natural Science Foundation of China Grant 81400805 (to P.W.) and National Institutes of Health Grant RO1-DK079968 (to R.M.) from the National Institute of Diabetes and Digestive and Kidney Diseases.
Funding AgencyGrant Number
National Science Foundation of China81400805
National Institute of Diabetes and Digestive and Kidney DiseasesRO1-DK079968
Subject Keywords:calcium; diabetic nephropathy; extracellular matrix; fibronectin; ion channel; mesangial cells
Issue or Number:11
PubMed Central ID:PMC4625675
Record Number:CaltechAUTHORS:20150325-074804965
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Official Citation:Store–Operated Ca2+ Channels in Mesangial Cells Inhibit Matrix Protein Expression Peiwen Wu, Yanxia Wang, Mark E. Davis, Jonathan E. Zuckerman, Sarika Chaudhari, Malcolm Begg, and Rong Ma JASN November 2015 26: 2691-2702; published ahead of print March 18, 2015, doi:10.1681/ASN.2014090853
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:56051
Deposited By: Ruth Sustaita
Deposited On:25 Mar 2015 16:08
Last Modified:10 Nov 2021 20:53

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