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  3. The ubiquitination of CKIP-1 mediated by Src aggravates diabetic renal fibrosis (original article)

The ubiquitination of CKIP-1 mediated by Src aggravates diabetic renal fibrosis (original article)

  • Biochem Pharmacol. 2022 Dec:206:115339. doi: 10.1016/j.bcp.2022.115339.
Yan Yang 1,  Haiming Xiao 2,  Zeyuan Lin 2,  Rui Chen 2,  Shanshan Li 2,  Chuting Li 2,  Xiaohong Sun 2,  Ziqing Hei 3,  Wenyan Gong 4,  Heqing Huang 5
Affiliations

Affiliations

  • 1 Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; School of Pharmaceutical Sciences, Guangdong Medical University, Zhanjiang 524032, China.
  • 2 Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
  • 3 Department of Anesthesiology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China. Electronic address: [email protected].
  • 4 Department of Clinical Medicine, medical school, Hangzhou Normal University, Hangzhou 310000, China. Electronic address: [email protected].
  • 5 Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: [email protected].
PMID: 36347273 DOI: 10.1016/j.bcp.2022.115339
Abstract

Renal chronic inflammation is an important hallmark of diabetic renal fibrosis. Casein Kinase 2 interacting protein 1 (CKIP-1) performs a nephroprotective role in the pathogenesis of diabetic nephropathy (DN), which is dramatically decreased in diabetic kidneys. However, whether CKIP-1 regulates inflammation to ameliorate renal fibrosis remains unclear and it is interesting to clarify the degradation mechanism of CKIP-1. Here, we identified CKIP-1 expression was down-regulated in diabetic kidneys and knockout (KO) of CKIP-1 increased c-Jun expression and extra cellular matrix (ECM) in kidneys of normal mice, and knockout (KO) of CKIP-1 further exacerbated renal inflammatory fibrosis in diabetic mice. Moreover, the activated Src kinase interacted with CKIP-1 at Lys252 and increased K48 linked polyubiquitination and Proteasome degradation of CKIP-1 in HG induced GMCs and diabetic kidneys. Mechanistically, Src facilitating the binding of c-Cbl with CKIP-1 by promoting the phosphorylation of c-Cbl, thereby increasing Cbl-mediated ubiquitination of CKIP-1 to down-regulate CKIP-1 protein expression. Thus, our study highlighted the anti-inflammation role of CKIP-1 and clarified the mechanism of CKIP-1 degradation in DN.

Keywords

CKIP-1; Diabetic nephropathy; Phosphorylation; Src kinase; Ubiquitination; c-Cbl.

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