Shihu-Yuye Decoction, a novel Chinese medicine formula, in treating diabetic nephropathy and the underlying mechanisms

Abstract

Diabetic nephropathy (DN), which is a major microvascular diabetic complication, is the deterioration of kidney function and the leading cause of end-stage renal disease (ESRD). Persistent hyperglycemia is the major reason of kidney dysfunction associated with diabetes mellitus. Statistics showed that there are over 246 million diabetic patients worldwide in 2007 and likely to increase to 380 million by 2025. Approximately 40% diabetic patients may result in DN. However, current treatment to DN is limited. Thus, it is important to develop alternative treatment to DN.

Report showed that DN can be improved by nourishing kidney Yin through Chinese medicine. Yuye Decoction (YYD) is a classic Chinese medicine formula. Dendrobium officinale (DO) can nourish kidney Yin. It is hypothesized that the combination of DO and YYD to form a Shihu-Yuye Decoction (DOY) can treat DN. TGF-β1 and ERK1/2 signaling pathway are crucial in the initiation and progression of DN. My study aims to 1) conduct a systematic review to identify potential single Chinese medicine which have therapeutic effect on treating DN; 2) conduct network pharmacology to identify potential targets and pathways for DO and YYD; 3) demonstrate the therapeutic effects of DOY by studying the mechanisms of the ERK1/2 and TGF-β1/Smad signaling pathways in the kidney.

In the literature review, it was showed that single Chinese medicine is effective in improving symptom of DN through different signaling pathways. There was strong evidence to support the use of DO and YYD in treating diabetes and its complications. Meta-analysis of RCT and animal studies showed that Chinese medicine decoctions are effective in treating DN and controlling blood glucose was the major objective of the TCM treatment. Network pharmacology of DO and YYD further revealed the active ingredients, target genes and potential signaling pathways in treating DN respectively.

In vitro study, DOY was demonstrated to inhibit the HG-induced excessive SV40 MES 13 cell proliferation and TGF-β1/Smad signaling pathway as well as to inhibit ERK and Akt. In vivo, DOY treatment group abolished the gain in body weight and blood glucose in a dose-dependent manner. The biochemical indexes such as food consumption, water consumption, body weight, fasting blood glucose, oral glucose tolerance test and urine albumin were significantly decreased after 12 weeks DOY administration. Histopathological examination showed that DOY was protective for renal damage. Western blot and immunohistochemical analysis suggested that DOY treatment downregulated TGF-β1 and ERK expression levels. Moreover, DOY inhibited TGF-β1-induced Smad2/3 phosphorylation. 1.0 g/kg DOY showed the most significant therapeutic effect on STZ-induced diabetic rats, indicating that it might be an alternative treatment for DN.

In conclusion, this is the first study systematically investigated Chinese medicine and particular DOY, a novel Chinese medicine formula, in treating DN and the underlying mechanisms. My study suggested that DOY improved renal function and relieve renal damage of DN through inhibiting TGF-β1/ Smad and ERK1/2 signaling pathway.