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Cpd-42 protects against calcium oxalate nephrocalcinosis-induced renal injury and inflammation by targeting RIPK3-mediated necroptosis

Affiliation
Department of Urology ,The First Affiliated Hospital of Anhui Medical University ,Hefei ,China
Hou, Bingbing;
Affiliation
The Key Laboratory of Anti-inflammatory of Immune Medicines ,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province ,Anhui Institute of Innovative Drugs ,School of Pharmacy ,Ministry of Education ,Anhui Medical University ,Hefei ,China
Liu, Mingming;
Affiliation
Department of Urology ,The First Affiliated Hospital of Anhui Medical University ,Hefei ,China
Chen, Yang;
Affiliation
The Key Laboratory of Anti-inflammatory of Immune Medicines ,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province ,Anhui Institute of Innovative Drugs ,School of Pharmacy ,Ministry of Education ,Anhui Medical University ,Hefei ,China
Ni, Weijian;
Affiliation
The Key Laboratory of Anti-inflammatory of Immune Medicines ,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province ,Anhui Institute of Innovative Drugs ,School of Pharmacy ,Ministry of Education ,Anhui Medical University ,Hefei ,China
Suo, Xiaoguo;
Affiliation
Department of Urology ,The First Affiliated Hospital of Anhui Medical University ,Hefei ,China
Xu, Yuexian;
Affiliation
Department of Urology ,The First Affiliated Hospital of Anhui Medical University ,Hefei ,China
He, Qiushi;
Affiliation
The Key Laboratory of Anti-inflammatory of Immune Medicines ,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province ,Anhui Institute of Innovative Drugs ,School of Pharmacy ,Ministry of Education ,Anhui Medical University ,Hefei ,China
Meng, Xiaoming;
Affiliation
Department of Urology ,The First Affiliated Hospital of Anhui Medical University ,Hefei ,China
Hao, Zongyao

Calcium oxalate (CaOx) crystals, as the predominant component of human kidney stones, can trigger excessive cell death and inflammation of renal tubular epithelial cells, involved in the pathogenesis of nephrocalcinosis. Necroptosis mediated by receptor-interacting protein kinase 3 (RIPK3) serves a critical role in the cytotoxicity of CaOx crystals. Here, we assessed the therapeutic potential of a novel RIPK3 inhibitor, compound 42 (Cpd-42), for CaOx nephrocalcinosis by comparison with dabrafenib, a classic RIPK3 inhibitor. Our results demonstrated that Cpd-42 pretreatment attenuated CaOx crystals-induced renal tubular epithelial cell (TEC) injury by inhibiting necroptosis and inflammation in vitro and in vivo . Furthermore, in an established mouse model of CaOx nephrocalcinosis, Cpd-42 also reduced renal injury while improving the impaired kidney function and intrarenal crystal deposition. Consistent with this finding, Cpd-42 was confirmed to exhibit superior inhibition of necroptosis and protection against renal TEC injury compared to the classic RIPK3 inhibitor dabrafenib in vitro and in vivo . Mechanistically, RIPK3 knockout (KO) tubular epithelial cells pretreated with Cpd-42 did not show further enhancement of the protective effect on crystals-induced cell injury and inflammation. We confirmed that Cpd-42 exerted protective effects by specifically targeting and inhibiting RIPK3-mediated necroptosis to block the formation of the RIPK1-RIPK3 necrosome. Taken together, targeted inhibition of RIPK3-mediated necroptosis with Cpd-42 may provide a potential therapeutic approach for CaOx nephrocalcinosis.

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License Holder: Copyright © 2022 Hou, Liu, Chen, Ni, Suo, Xu, He, Meng and Hao.

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