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

Area of Science:

• Nephrology
• Molecular Biology
• Biochemistry

Background:

• Diabetic nephropathy (DN) is characterized by renal chronic inflammation and fibrosis.
• Casein kinase 2 interacting protein 1 (CKIP-1) has a protective role in DN but is downregulated in diabetic kidneys.
• The precise role of CKIP-1 in regulating inflammation and its degradation mechanism in DN remain unclear.

Purpose of the Study:

• To investigate the anti-inflammatory role of CKIP-1 in diabetic renal fibrosis.
• To elucidate the degradation mechanism of CKIP-1 in the context of diabetic nephropathy.
• To explore the interaction between CKIP-1, Src kinase, and c-Cbl in regulating renal fibrosis.

Main Methods:

• Analysis of CKIP-1 expression in diabetic kidneys and high glucose (HG)-induced glomerular mesangial cells (GMCs).
• Utilizing knockout (KO) mouse models to assess the impact of CKIP-1 deficiency on renal fibrosis and inflammation.
• Investigating the interaction between Src kinase, CKIP-1, and c-Cbl using co-immunoprecipitation and Western blotting in HG-induced GMCs and diabetic kidneys.

Main Results:

• CKIP-1 expression was significantly downregulated in diabetic kidneys.
• CKIP-1 KO mice exhibited increased c-Jun and extracellular matrix (ECM) expression, and exacerbated renal inflammatory fibrosis under diabetic conditions.
• Activated Src kinase phosphorylated and bound to CKIP-1, promoting its K48-linked polyubiquitination and proteasomal degradation via the c-Cbl E3 ligase, leading to reduced CKIP-1 protein levels.

Conclusions:

• CKIP-1 plays a crucial anti-inflammatory and nephroprotective role in diabetic nephropathy.
• Src-mediated phosphorylation and subsequent c-Cbl-dependent ubiquitination represent a key degradation pathway for CKIP-1 in DN.
• Targeting CKIP-1 degradation may offer a therapeutic strategy for mitigating renal fibrosis in diabetic nephropathy.