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Blockade of KCa3.1 potassium channels protects against cisplatin-induced acute kidney injury

  • Organ Toxicity and Mechanisms
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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.

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Acknowledgments

This study was supported by a research Grant from the Ministry of Science and Technology (No. 102-2320-B-255-006-MY3) and a partial Grant from the Department of Chinese Medicine and Pharmacy, Ministry of Health and Welfare, Executive Yuan, Taipei, Taiwan (No. 102-RD-002).

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Authors and Affiliations

  1. Graduate Institute of Life Sciences, National Defense Medical Center, No. 161, Sec. 6, Minquan E. Rd., Neihu Dist., Taipei, Taiwan, R.O.C.

    Cheng-Lung Chen & Li-Heng Pao

  2. Graduate Institute of Veterinary Pathology, National Chung Hsing University, No. 250, Guoguang Rd., South Dist., Taichung, Taiwan, R.O.C.

    Jiunn-Wang Liao

  3. School of Pharmacy, National Defense Medical Center, No. 161, Sec. 6, Minquan E. Rd., Neihu Dist., Taipei, Taiwan, R.O.C.

    Oliver Yoa-Pu Hu & Li-Heng Pao

  4. 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.

    Li-Heng Pao

  5. 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.

    Li-Heng Pao

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  1. Cheng-Lung Chen
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Chen, CL., Liao, JW., Hu, O.YP. et al. Blockade of KCa3.1 potassium channels protects against cisplatin-induced acute kidney injury. Arch Toxicol 90, 2249–2260 (2016). https://doi.org/10.1007/s00204-015-1607-5

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  • DOI: https://doi.org/10.1007/s00204-015-1607-5

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