Journal
BIOCHEMICAL PHARMACOLOGY
Volume 206, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2022.115339
Keywords
CKIP-1; Diabetic nephropathy; Src kinase; Phosphorylation; c-Cbl; Ubiquitination
Categories
Funding
- National Natural Science Foundation of China
- Key Project of Guangdong Province, China
- [81770816]
- [81973375]
- [81900745]
- [2020B1111100004]
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CKIP-1 plays a nephroprotective role in diabetic nephropathy by regulating inflammation and its down-regulation exacerbates renal inflammatory fibrosis. Src kinase interacts with CKIP-1 and promotes its ubiquitination and protein degradation.
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 pro-moting 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.
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