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

Yan Yang, Haiming Xiao, Zeyuan Lin, Rui Chen, Shanshan Li, Chuting Li, Xiaohong Sun, Ziqing Hei, Wenyan Gong, Heqing Huang

Biochemical pharmacology 2022 Dec

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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. Copyright © 2022 Elsevier Inc. All rights reserved.

Citation

Yan Yang, Haiming Xiao, Zeyuan Lin, Rui Chen, Shanshan Li, Chuting Li, Xiaohong Sun, Ziqing Hei, Wenyan Gong, Heqing Huang. The ubiquitination of CKIP-1 mediated by Src aggravates diabetic renal fibrosis (original article). Biochemical pharmacology. 2022 Dec;206:115339