title: Blockade of Orai1 Store-Operated Calcium Entry Protects against Renal Fibrosis.
abstract: Evidence supports an important role of Ca2+release-activated Ca2+channel protein 1 (Orai1)-mediated Ca2+entry in the development of renal fibrosis, a common pathologic feature of CKDs that lead to ESRD, but the molecular mechanisms remain unclear. We determined the role of Orai1 calcium channel in renal fibrosis induced by high-fat diet and by unilateral ureteral obstruction. Mouse kidneys with fibrosis had higher levels of Orai1 protein expression than did kidneys without fibrosis. In vivo knockdown of Orai1 with adenovirus harboring Orai1-short hairpin RNA or inhibition of Orai1 with SKF96365 dramatically prevented renal fibrosis and significantly decreased protein expression of fibronectin, α‑smooth muscle actin, and TGF‑β1 in the kidney cortex of ApoE-/-mice on a high-fat diet and in the obstructed kidneys of mice with unilateral ureteral obstruction. Compared with kidney biopsy specimens of patients with glomerular minimal change disease, those of patients with fibrotic nephropathy had higher expression levels of Orai1. In cultured human proximal tubule epithelial cells (HK2), knockdown of Orai1 Ca2+channel with adenovirus-Orai1-short hairpin RNA markedly inhibited TGF-β1-induced intracellular Ca2+influx and phosphorylation of smad2/3. Knockdown or blockade of the Orai1 Ca2+channel in HK2 cells also prevented epithelial-to-mesenchymal transition induced by TGF‑β1. In conclusion, blockade of the Orai1 Ca2+channel prevented progression of renal fibrosis in mice, likely by suppressing smad2/3 phosphorylation and TGF-β1-induced epithelial-to-mesenchymal transition. These results render the Orai1 Ca2+channel a potential therapeutic target against renal fibrosis.
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center and.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Mai
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center and.
authors.forename: Jinyan
authors.initials: J
authors.lastname: Shang
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center and.
authors.forename: Sijia
authors.initials: S
authors.lastname: Liang
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center and.
authors.forename: Beixin
authors.initials: B
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center and.
authors.forename: Jiani
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; and.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; and.
authors.forename: Renfei
authors.initials: R
authors.lastname: Luo
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center and.
authors.forename: Feiran
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center and.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center and.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Lv
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; and.
authors.forename: Chunling
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Xinling
authors.initials: X
authors.lastname: Liang
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; and zhoujg@mail.sysu.edu.cn wangwd6@mail.sysu.edu.cn.
authors.forename: Weidong
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center and zhoujg@mail.sysu.edu.cn wangwd6@mail.sysu.edu.cn.
authors.forename: Jiaguo
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000502:physiology*; D002478:Cells, Cultured; D005355:Fibrosis / Q000517:prevention & control; D007093:Imidazoles / Q000494:pharmacology*; D007668:Kidney / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071740:ORAI1 Protein / Q000037:antagonists & inhibitors*
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007093:Imidazoles; D000071740:ORAI1 Protein; C520430:Orai1 protein, mouse; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D002118:Calcium
keywords: EMT; Orai1; renal fibrosis