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[Oxymatrine improves renal fibrosis and inflammation in diabetic rats by modulating CHK1/2 phosphorylation]
1Department of Pathophysiology, Basic Medical College, Guizhou Medical University/ Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research of Common Chronic Diseases, Guiyang 550025, China.
Objective:
To explore the role of cell cycle checkpoint kinase 1/2 (CHK1/2) in mediating the inhibitory effect of oxymatrine (OMT) against renal inflammation and fibrosis in diabetic rats.
Methods:
SD rats were randomly divided into normal control group, diabetes model group (DM) and OMT treatment group (n=6). HE and Masson staining were used to observe histopathological changes of the renal tissue, and the expressions of CHK1, CHK2, p-CHK1 and p-CHK2 were localized by immunohistochemical staining. The contents of interleukin-6 (IL-6) and IL-1β in the renal tissue were detected using ELISA, and the expression levels of CHK1, CHK2, p-CHK1, p-CHK2, type Ⅲ collagen (Col-Ⅲ), type Ⅳ collagen (Col-Ⅳ), and fibronectin (FN) were determined using Western blotting. The changes in the expressions of CHK1, CHK2, p-CHK1, p-CHK2, Col-Ⅲ, Col-Ⅳ and FN proteins were also examined with Western blotting in NRK-52E cells in response to high glucose exposure, OMT treatment and siRNA-mediated CHK1/2 knockdown.
Results:
In diabetic rats, OMT treatment significantly decreased the levels of blood glucose, serum creatinine and 24 h urinary protein (P < 0.05) and obviously improved inflammatory cell infiltration and fibrosis phenotype in the renal tissue (P < 0.05). CHK1 and CHK2 were mainly expressed in the cytoplasm and nuclei of renal tubule cells, and their phosphorylation levels were significantly higher in DM group than in the control group and OMT group. OMT treatment significantly decreased the protein expression levels of p-CHK1, p-CHK2, Col-Ⅲ, Col-Ⅳ and FN in the renal tissue of diabetic rats and in NRK-52E cells exposed to high glucose (P < 0.05). In NRK-52E cells, CHK1/2 knockdown resulted in significant reduction of the protein expressions of p-CHK1/2, Col-Ⅲ, Col-Ⅳ and FN (P < 0.05).
Conclusion:
The inhibitory effects of OMT against renal inflammation and fibrosis in diabetic rats are mediated probably by lowered phosphorylation levels of CHK1 and CHK2, which result in reduced release of the downstream inflammatory mediators and decreased secretion and deposition of extracellular matrix.
Insights
Oxymatrine (OMT) reduces diabetic kidney inflammation and fibrosis by decreasing cell cycle checkpoint kinase 1/2 (CHK1/2) phosphorylation. This action lowers inflammatory mediators and extracellular matrix deposition in diabetic rats.
Area of Science:
- Nephrology
- Pharmacology
- Cell Biology
Background:
- Diabetic nephropathy is characterized by renal inflammation and fibrosis.
- Cell cycle checkpoint kinases (CHK1/2) play a role in cellular stress responses.
- Oxymatrine (OMT) is a traditional Chinese medicine with potential therapeutic properties.
Purpose of the Study:
- To investigate the role of CHK1/2 in OMT's anti-inflammatory and anti-fibrotic effects in diabetic rat kidneys.
- To elucidate the molecular mechanisms underlying OMT's action.
Main Methods:
- Diabetic rat models and NRK-52E cells were treated with OMT.
- Histopathological changes were assessed using HE and Masson staining.
- Protein expression of CHK1, CHK2, phosphorylated CHK1/2, collagen, and fibronectin was analyzed via immunohistochemistry and Western blotting.
- Inflammatory cytokines IL-6 and IL-1β were measured using ELISA.
- CHK1/2 knockdown was performed using siRNA.
Main Results:
- OMT treatment significantly improved renal histopathology, reduced blood glucose, serum creatinine, and urinary protein in diabetic rats.
- Phosphorylation levels of CHK1/2 were elevated in diabetic kidneys and high glucose-treated cells, and reduced by OMT.
- OMT decreased the expression of collagen and fibronectin in diabetic rat kidneys and high glucose-treated cells.
- CHK1/2 knockdown mimicked OMT's effects, reducing inflammatory and fibrotic markers.
Conclusions:
- OMT exerts protective effects against renal inflammation and fibrosis in diabetic rats.
- These effects are likely mediated by the downregulation of CHK1/2 phosphorylation.
- Reduced CHK1/2 phosphorylation leads to decreased inflammatory mediator release and extracellular matrix deposition.
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