title: Blockade of KCa3.1 potassium channels protects against cisplatin-induced acute kidney injury.
abstract: Tubular cell apoptosis significantly contributes to cisplatin-induced acute kidney injury (AKI) pathogenesis. Although KCa3.1, a calcium-activated potassium channel, participates in apoptosis, its involvement in cisplatin-induced AKI is unknown. Here, we found that cisplatin treatment triggered an early induction of KCa3.1 expression associated with HK-2 cell apoptosis, the development of renal tubular damage, and apoptosis in mice. Treatment with the highly selective KCa3.1 blocker TRAM-34 suppressed cisplatin-induced HK-2 cell apoptosis. We further assessed whether KCa3.1 mediated cisplatin-induced AKI in genetic knockout and pharmacological blockade mouse models. KCa3.1 deficiency reduced renal function loss, renal tubular damage, and the induction of the apoptotic marker caspase-3 in the kidneys of cisplatin-treated KCa3.1 (-/-) mice. Pharmacological blockade of KCa3.1 by TRAM-34 similarly attenuated cisplatin-induced AKI in mice. Furthermore, we dissected the mechanisms underlying cisplatin-induced apoptosis reduction via KCa3.1 blockade. We found that KCa3.1 blockade attenuated cytochrome c release and the increase in the intrinsic apoptotic mediators Bax, Bak, and caspase-9 after cisplatin treatment. KCa3.1 blocking inhibited the cisplatin-induced activation of the endoplasmic reticulum (ER) stress mediator caspase-12, which is independent of calcium-dependent protease m-calpain activation. Taken together, KCa3.1 blockade protects against cisplatin-induced AKI through the attenuation of apoptosis by interference with intrinsic apoptotic and ER stress-related mediators, providing a potential target for the prevention of cisplatin-induced AKI.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, No. 161, Sec. 6, Minquan E. Rd., Neihu Dist., Taipei, Taiwan, R.O.C.
authors.forename: Cheng-Lung
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Graduate Institute of Veterinary Pathology, National Chung Hsing University, No. 250, Guoguang Rd., South Dist., Taichung, Taiwan, R.O.C.
authors.forename: Jiunn-Wang
authors.initials: JW
authors.lastname: Liao
authors.affiliation: School of Pharmacy, National Defense Medical Center, No. 161, Sec. 6, Minquan E. Rd., Neihu Dist., Taipei, Taiwan, R.O.C.
authors.forename: Oliver Yoa-Pu
authors.initials: OY
authors.lastname: Hu
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, No. 161, Sec. 6, Minquan E. Rd., Neihu Dist., Taipei, Taiwan, R.O.C.. paolh@mail.cgust.edu.tw.|School of Pharmacy, National Defense Medical Center, No. 161, Sec. 6, Minquan E. Rd., Neihu Dist., Taipei, Taiwan, R.O.C.. paolh@mail.cgust.edu.tw.|Graduate Institute of Health-Industry Technology, Chang Gung University of Science and Technology, No. 261, Wenhua 1st Rd., Guishan Dist., Taoyuan, Taiwan, R.O.C.. paolh@mail.cgust.edu.tw.|Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, No. 261, Wenhua 1st Rd., Guishan Dist., Taoyuan, Taiwan, R.O.C.. paolh@mail.cgust.edu.tw.
authors.forename: Li-Heng
authors.initials: LH
authors.lastname: Pao
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D019610:Cytoprotection; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011720:Pyrazoles / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D051017:Apoptosis Regulatory Proteins; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; C496925:Kcnn4 protein, mouse; D026902:Potassium Channel Blockers; D011720:Pyrazoles; C411671:TRAM 34; D002945:Cisplatin
keywords: Acute kidney injury; Cisplatin; KCa3.1 potassium channel; Tubular cell apoptosis