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

Bingbing Hou; Mingming Liu; Yang Chen; Weijian Ni; Xiaoguo Suo; Yuexian Xu; Qiushi He; Xiaoming Meng; Zongyao Hao

doi:10.3389/fphar.2022.1041117

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

Front Pharmacol. 2022 Nov 3:13:1041117. doi: 10.3389/fphar.2022.1041117. eCollection 2022.

Authors

Bingbing Hou^{1

2

3}, Mingming Liu⁴, Yang Chen^{1

2

3}, Weijian Ni⁴, Xiaoguo Suo⁴, Yuexian Xu^{1

2

3}, Qiushi He^{1

2

3}, Xiaoming Meng⁴, Zongyao Hao^{1

2

3}

Affiliations

¹ Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
² Institute of Urology, Anhui Medical University, Hefei, China.
³ Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China.
⁴ 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.

Abstract

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.

Keywords: calcium oxalate; compound 42; inflammation; necroptosis; nephrocalcinosis; ripk3.