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Zhenqing recipe relieves diabetic nephropathy through the SIK1/SREBP-1c axis in type 2 diabetic rats.

ABSTRACT:

Background

Salt-inducible kinase 1 (SIK1) plays an important role in lipid metabolism, which inhibits lipid synthesis by directly phosphorylating multiple serine residue sites of sterol regulatory element-binding protein 1c (SREBP-1c). This study examined potential therapeutic effect of a Chinese herbal medicine Zhenqing Recipe (ZQR) and metformin on diabetic nephropathy and investigated whether the SIK1/SREBP-1c axis is involved.

Methods

The rat model of type 2 diabetes was developed by high-sucrose plus high fat diet for one month combined with low-dose Streptozocin intraperitoneal injection for three days, after which the presence of hyperglycemia and hyperlipidemia was examined to validate the model. The diabetic rats were then randomly allocated to diabetic groups treated by either ZQR or metformin, and normal rats receiving normal diet were included as a control group. Metabolic parameters, renal function, and renal triglyceride were examined and compared between groups.

Results

After a treatment of 12 weeks, ZQR and metformin significantly reduced serum glucose and triglyceride, inhibited diabetic nephropathy and improved renal function. The mRNA level of SIK1 was significantly lower in the diabetic rats than that in the control group, while the expression of SREBP-1c had an opposite pattern. However, after receiving ZQR or metformin treatment, the SIK1 level in diabetic rats increased and the SREBP-1c level was downregulated. Consistent results were observed at the protein level.

Conclusion

The data suggested that similar to metformin, ZQR could alleviate diabetic nephropathy through SIK1/SREBP-1c axis.

SUBMITTER: Liao Q

PROVIDER: S-EPMC8748144 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAs a compound Chinese medicine, Zhenqing Recipe (ZQR) has been shown to ameliorate hyperglycemia, hyperlipidemia, fatty liver and insulin resistance in patients with diabetes and diabetic rats. In this paper, we further examined the effect of ZQR on diabetes complicated by non-alcoholic fatty liver disease (NAFLD) and the underlying molecular mechanisms.MethodsDiabetic rats with NAFLD were developed by a high-fat diet (HFD) with low-dose streptozotocin (STZ) injection for 4 weeks. These rats were randomly separated into the diabetic model (DM), ZQR, metformin (Met), adenovirus expressing-salt-induced kinase 1 (Ad-SIK1) and adenovirus labeled with green fluorescent protein (Ad-GFP) groups. The effects on hepatic expression of gluconeogenic genes, glycolipid metabolism and pathological changes were subsequently detected.ResultsSerum glucose, triglycerides (TG), total cholesterol (TC) and hepatic TG were reduced in the ZQR group. The histopathological and immunohistochemical changes in the liver and pancreas in the ZQR group were significantly alleviated. The decrease of SIK1 expression was observed in the liver of diabetic rats induced by HFD and STZ. SIK1 overexpression in the liver relieved hyperglycemia, hyperlipidemia and fatty liver. Both the mRNA and protein levels of CREB-regulated transcription co-activator 2 (CRTC2), phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in the liver were drastically reduced, whereas those of SIK1 were markedly increased in the ZQR group compared to levels in the DM group. Compared with the DM group, Ser577 phosphorylation of SIK1 was obviously reduced in the liver, while T182 phosphorylation of SIK1 and S171 phosphorylation of CRTC2 were evidently increased in the Ad-SIK1, Met and ZQR groups.ConclusionsZQR ameliorates hepatic gluconeogenesis and lipid storage in diabetic rats induced by HFD and STZ by activating the SIK1/CRTC2 signaling pathway. Upregulating hepatic SIK1 by ZQR may represent an efficient strategy for treating diabetes with NAFLD.