CHIP protects against septic acute kidney injury by inhibiting NLRP3-mediated pyroptosis

Hao Zhang; Zebin Deng; Yilong Wang; Xiaoping Zheng; Lizhi Zhou; Shu Yan; Yinhuai Wang; Yingbo Dai; Yashpal S Kanwar; Fei Deng

doi:10.1016/j.isci.2023.107762

CHIP protects against septic acute kidney injury by inhibiting NLRP3-mediated pyroptosis

iScience. 2023 Aug 28;26(10):107762. doi: 10.1016/j.isci.2023.107762. eCollection 2023 Oct 20.

Authors

Hao Zhang¹, Zebin Deng¹, Yilong Wang², Xiaoping Zheng³, Lizhi Zhou¹, Shu Yan⁴, Yinhuai Wang¹, Yingbo Dai³, Yashpal S Kanwar⁵, Fei Deng^{1

6}

Affiliations

¹ Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
² Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
³ Department of Urology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China.
⁴ Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.
⁵ Departments of Pathology & Medicine, Northwestern University, Chicago, IL, USA.
⁶ Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.

Abstract

Septic acute kidney injury (S-AKI), the most common type of acute kidney injury (AKI), is intimately related to pyroptosis and oxidative stress in its pathogenesis. Carboxy-terminus of Hsc70-interacting protein (CHIP), a U-box E3 ligase, modulates oxidative stress by degrading its targeted proteins. The role of CHIP in S-AKI and its relevance with pyroptosis have not been investigated. In this study, we showed that CHIP was downregulated in renal proximal tubular cells in lipopolysaccharide (LPS)-induced S-AKI. Besides, the extent of redox injuries in S-AKI was attenuated by CHIP overexpression or activation but accentuated by CHIP gene disruption. Mechanistically, our work demonstrated that CHIP interacted with and ubiquitinated NLRP3 to promote its proteasomal degradation, leading to the inhibition of NLRP3/ACS inflammasome-mediated pyroptosis. In summary, this study revealed that CHIP ubiquitinated NLRP3 to alleviate pyroptosis in septic renal injuries, suggesting that CHIP might be a potential therapeutic target for S-AKI.

Keywords: Molecular medicine; Molecular physiology; Nephrology.