Abstract
Objective Diabetic kidney disease (DKD) is one of the most common chronic microvascular complications of diabetes; however, there remains a lack of effective therapeutic strategies. Yi Shen Pai Du Formula (YSPDF), a traditional Chinese medicine preparation, has been clinically used in treating chronic kidney disease (CKD) for more than 20 years. However, whether YSPDF has a therapeutic effect on DKD has not been studied. Methods This study was conducted to investigate the effect of YSPDF administration on db/db mice, a model of type 2 diabetes that develops DKD, and reveal its underlying mechanism of action through a high glucose- (HG-) induced renal injury cell model. Results We found that YSPDF significantly improved numerous biochemical parameters (fasting blood glucose, serum creatinine, blood urea nitrogen, 24 h urine total protein, total cholesterol, and total triglycerides) and ameliorated the abnormal histology and fibrosis of renal tissue. Moreover, the status of oxidative stress and levels of inflammatory cytokines (TNF-α, IL-6, IL-1β, and MCP-1) were markedly inhibited by YSPDF treatment. YSPDF treatment significantly mitigated renal fibrosis, with evidence suggesting that this was by inhibiting epithelial-to-mesenchymal transition (EMT) via suppression of the TGF-β1/Smad pathway. Interestingly, the expression of Nrf2, HO-1, and NQO1, proteins known to be associated with oxidative stress, were significantly increased upon administration of YSPDF. The levels of NLRP3 inflammasome proteins, including NLRP3, ASC, caspase-1, and cleaved caspase-1 were decreased in the YSPDF-treated group. Cell experiments showed that YSPDF inhibited EMT and the NLRP3 inflammasome in HG-exposed HK-2 cells, possibly via activation of Nrf2. Conclusion Our study indicates that YSPDF may ameliorate renal damage in db/db mice via inhibition of oxidative stress, inflammation, and EMT, with the mechanism potentially being related to the activation of the Nrf2 pathway.
Highlights
Diabetic kidney disease (DKD), known as diabetic nephropathy (DN), is one of the most common chronic microvascular complications of diabetes and is the leading cause of end-stage renal failure (ESRD)
Results indicated that Yi Shen Pai Du Formula (YSPDF) was able to reduce the fasting blood glucose levels of db/db mice and potentially might have a protective effect on kidney
Our results found that the levels of GSH, SOD, and CAT activities were downregulated in the kidneys of untreated DKD mice, whereas reactive oxygen species (ROS) and MDA increased, demonstrating severe oxidative damage occurring in the kidneys of db/db mice
Summary
Diabetic kidney disease (DKD), known as diabetic nephropathy (DN), is one of the most common chronic microvascular complications of diabetes and is the leading cause of end-stage renal failure (ESRD). Developing highly effective and low-toxic drugs that can prevent the occurrence and progression of DKD has become a serious medical challenge. Tubulointerstitial fibrosis is a crucial pathological alteration underlying the progression of DKD [4, 5]. Epithelialto-mesenchymal transition (EMT), characterized by a loss of epithelial phenotype and a gain of profibrotic features, plays a crucial role in the development and progression of tubulointerstitial fibrosis [4]. When EMT is activated, the kidney fibroblasts have been shown to translate into myofibroblasts, secreting excessive extracellular matrix (ECM) and eventually causing the development of fibrosis [5]. It has been demonstrated that transforming growth factor-β1 (TGF-β1) is able to induce EMT activation in renal tubular epithelial cells [6, 7]. Inhibiting EMT via the TGF-β1/Smad pathway might be an effective therapeutic target for DKD
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