title: Store-Operated Ca2+ Channels in Mesangial Cells Inhibit Matrix Protein Expression.
abstract: 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.
authors: Department of Integrative Physiology and Anatomy and Cardiovascular Research Institute, University of North Texas Health Science Center, Fort Worth, Texas; Department of Endocrinology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, People's Republic of China;
authors: Peiwen
authors: P
authors: Wu
authors: Department of Integrative Physiology and Anatomy and Cardiovascular Research Institute, University of North Texas Health Science Center, Fort Worth, Texas;
authors: Yanxia
authors: Y
authors: Wang
authors: Chemical Engineering, California Institute of Technology, Pasadena, California; and.
authors: Mark E
authors: ME
authors: Davis
authors: Chemical Engineering, California Institute of Technology, Pasadena, California; and.
authors: Jonathan E
authors: JE
authors: Zuckerman
authors: Department of Integrative Physiology and Anatomy and Cardiovascular Research Institute, University of North Texas Health Science Center, Fort Worth, Texas;
authors: Sarika
authors: S
authors: Chaudhari
authors: Respiratory Therapy Area Unit, Medicines Research Center, GlaxoSmithKline, Stevenage, United Kingdom.
authors: Malcolm
authors: M
authors: Begg
authors: Department of Integrative Physiology and Anatomy and Cardiovascular Research Institute, University of North Texas Health Science Center, Fort Worth, Texas; rong.ma@unthsc.edu.
authors: Rong
authors: R
authors: Ma
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000737:chemistry; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D024141:Collagen Type IV / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D005920:Glomerular Mesangium / Q000378:metabolism; D005947:Glucose / Q000737:chemistry; D006801:Humans; D007477:Ions / Q000737:chemistry; D007672:Kidney Cortex / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D050527:Mesangial Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry; D009363:Neoplasm Proteins / Q000378:metabolism; D000071740:ORAI1 Protein; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071737:Stromal Interaction Molecule 1; D019284:Thapsigargin / Q000737:chemistry; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C538758:2-aminoethyl diphenylborinate; D001896:Boron Compounds; D015220:Calcium Channels; D024141:Collagen Type IV; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D007477:Ions; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C520430:Orai1 protein, mouse; C103530:STIM1 protein, human; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D053773:Transforming Growth Factor beta1; D019284:Thapsigargin; D005947:Glucose; D002118:Calcium
keywords: calcium; channel; diabetic nephropathy; extracellular matrix; fibronectin; ion; mesangial cells