TY - JOUR
T1 - Store-operated Ca2+ channels in mesangial cells inhibit matrix protein expression
AU - Wu, Peiwen
AU - Wang, Yanxia
AU - Davis, Mark E.
AU - Zuckerman, Jonathan E.
AU - Chaudhari, Sarika
AU - Begg, Malcolm
AU - Ma, Rong
N1 - Publisher Copyright:
Copyright © 2015 by the American Society of Nephrology.
PY - 2015/11
Y1 - 2015/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84961332299&partnerID=8YFLogxK
U2 - 10.1681/ASN.2014090853
DO - 10.1681/ASN.2014090853
M3 - Article
C2 - 25788524
AN - SCOPUS:84961332299
SN - 1046-6673
VL - 26
SP - 2691
EP - 2702
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 11
ER -