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, Rong Ma

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

Abstract

Accumulation of extracellularmatrix derived fromglomerular mesangial cells is an early feature of diabetic nephropathy. Ca2+ signals mediated by store-operated Ca2+ channels regulate protein production in a variety of cell types. The aim of this study was to determine the effect of store-operated Ca2+ channels in mesangial cells on extracellularmatrix protein expression. In cultured humanmesangial cells, activation of store-operated Ca2+ 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 Ca2+ channels in mesangial cells negatively regulate extracellular matrix protein expression in the kidney, which may serve as an endogenous renoprotective mechanism in diabetes.

Original languageEnglish
Pages (from-to)2691-2702
Number of pages12
JournalJournal of the American Society of Nephrology
Volume26
Issue number11
DOIs
StatePublished - 1 Nov 2015

Fingerprint

Mesangial Cells
Fibronectins
Collagen
Proteins
Thapsigargin
Small Interfering RNA
Kidney
Dependovirus
Extracellular Matrix Proteins
Diabetic Nephropathies
Angiotensin II
Nanoparticles
Cultured Cells
Glucose
Messenger RNA

Cite this

Wu, Peiwen ; Wang, Yanxia ; Davis, Mark E. ; Zuckerman, Jonathan E. ; Chaudhari, Sarika ; Begg, Malcolm ; Ma, Rong. / Store-operated Ca2+ channels in mesangial cells inhibit matrix protein expression. In: Journal of the American Society of Nephrology. 2015 ; Vol. 26, No. 11. pp. 2691-2702.
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abstract = "Accumulation of extracellularmatrix derived fromglomerular mesangial cells is an early feature of diabetic nephropathy. Ca2+ signals mediated by store-operated Ca2+ channels regulate protein production in a variety of cell types. The aim of this study was to determine the effect of store-operated Ca2+ channels in mesangial cells on extracellularmatrix protein expression. In cultured humanmesangial cells, activation of store-operated Ca2+ 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 Ca2+ channels in mesangial cells negatively regulate extracellular matrix protein expression in the kidney, which may serve as an endogenous renoprotective mechanism in diabetes.",
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Store-operated Ca2+ channels in mesangial cells inhibit matrix protein expression. / Wu, Peiwen; Wang, Yanxia; Davis, Mark E.; Zuckerman, Jonathan E.; Chaudhari, Sarika; Begg, Malcolm; Ma, Rong.

In: Journal of the American Society of Nephrology, Vol. 26, No. 11, 01.11.2015, p. 2691-2702.

Research output: Contribution to journalArticleResearchpeer-review

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