Abstract
Xiexin decoction, a herbal therapeutic agent commonly used in traditional Chinese medicine, is recognized for its beneficial effects on diabetic nephropathy exerted through the combined action of multiple components, including Rhizoma Coptidis alkaloids (A), Radix et Rhizoma Rhei polysaccharides (P), and Radix Scutellaria flavones (F). Our previous studies have shown that a combination of A, P, and F (APF) exhibits renoprotective effects against diabetic nephropathy. This study was aimed at determining the effects of APF on renal fibrosis in diabetic nephropathy and elucidating the underlying molecular mechanisms. To evaluate the effects of APF, in vivo, db/db diabetic mice were orally administered a low or high dose of APF (300 or 600 mg/kg, respectively) once a day for 8 weeks. We evaluated the blood and urine indices of metabolic and renal function, renal tissue histopathology, renal inflammation, and fibrosis. APF treatment significantly ameliorated glucose and lipid metabolism dysfunction, decreased urinary albumin excretion, normalized creatinine clearance, and reduced the morphological changes in renal tissue. Additionally, APF administration in db/db diabetic mice reduced the elevated levels of renal inflammation mediators such as intercellular adhesion molecule-1, monocyte chemotactic protein-1, tumor necrosis factor-α, interleukin-1β, and active nuclear factor κB (NF-κB). APF treatment also reduced type I and IV collagen, transforming growth factor-β1 (TGF-β1), and TGF-β1 type II receptor expression levels, and decreased the phosphorylation of Smad2/3 in the kidneys of db/db diabetic mice. These results suggest that APF reduces renal fibrosis in diabetic nephropathy through the NF-κB and TGF-β1/Smad signaling pathways. In vitro, APF treatment reduced cell proliferation and protein expression of α-smooth muscle actin, collagen I, TGF-β1 and NF-κB in mesangial cells cultured with high glucose concentrations. Our findings indicate that treatment with multi-component herbal therapeutic formulations may be a useful approach for the treatment of diabetic nephropathy.
Highlights
Diabetes is a chronic metabolic syndrome and its vascular complications are responsible for morbidity and mortality in diabetic patients [1]
The levels of Fasting blood glucose (FBG), serum insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and serum triglycerides were markedly increased in control untreated db/db mice compared to the corresponding values in db/m mice
In our current study using a db/db mouse model of type 2 diabetes, we demonstrate that APF treatment has potential for use in the amelioration of glucose and lipid metabolism disorders, and can decrease urinary albumin excretion
Summary
Diabetes is a chronic metabolic syndrome and its vascular complications are responsible for morbidity and mortality in diabetic patients [1]. Despite the widespread use of numerous therapeutic approaches focused on managing hyperglycemia and high blood pressure, high proportion of diabetic patients still suffer from progressive and severe renal injury [3,4,5]. Results from diabetic animal models and human patients have demonstrated that persistent hyperglycemia increases renal TGF-β1 expression [8, 9]. Inhibiting TGF-β1/Smad pathway may have therapeutic potential against diabetic renal fibrosis. Several reports have suggested that the use of anti-TGF-β monoclonal antibody [12] and TGF-β receptor inhibitor [13] to block the TGF-β pathway could attenuate renal fibrosis in diabetic animal models, but may increase renal inflammation [13]. There is great potential for identification of novel anti-DN drugs through the evaluation of the inhibition of NF-κB and TGF-β1/Smad signaling pathways by TCM agents
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