2-3-5-4--tetrahydroxystilbene-2-o-glucopyranoside and Albuminuria

2,3,5,4'-Tetrahydroxystilbene-2-O-β-d-glucoside (THSG) is an active compound extracted from Polygonum multiflorum Thunb. This herb and radix Polygoni Multiflori preparata have been used to treat arteriosclerosis, hyperlipidemia, hypercholesterolemia, and diabetes for thousands of years. This study aimed to investigate the protective effects of THSG in an Adriamycin (AD)-induced focal segmental glomerulosclerosis (FSGS) mouse model and the underlying mechanisms in an in vitro system. Mice were treated with THSG (2.5 and 10 mg/kg, oral gavage) for 24 consecutive days. On the third day, mice were intravenously given a single dose of AD (10 mg/kg). At the end of the experiment, plasma and kidney samples were harvested to evaluate the therapeutic effects of THSG. The potential mechanisms of THSG in protecting against AD-induced cytotoxicity were examined using a real-time polymerase chain reaction, immunoblots, lactate dehydrogenase assay, and a cellular oxidized-thiol detection system in a mouse mesangial cell line. In this study, THSG showed concentration-dependent protective effects in ameliorating the progression of AD-induced FSGS. THSG suppressed albuminuria and hypercholesterolemia and reduced the status of lipid peroxidation in urine, plasma, and kidney tissue samples. Furthermore, THSG protected against podocyte damage, reduced renal fibrotic gene expressions, and alleviated the severity of glomerulosclerosis. Treatment of mouse mesangial cells with THSG induced nuclear factor erythroid-derived 2-like 2 (Nrf2) nuclear translocation, increased heme oxygenase-1 and NAD(P)H:quinone oxidoreductase (NQO)-1 gene expressions, and reduced cellular thiol oxidation and resistance to AD-induced cytotoxicity. Silencing Nrf2 and its repressor protein, Kelch-like ECH-associated protein 1 (Keap1), abolished these protective effects of THSG. In conclusion, THSG can play a protective role in ameliorating the progression of FSGS in a mouse model through activation of the Nrf2-Keap1 antioxidant pathway. Although a well-designed therapeutic study is needed, THSG may be applied to manage chronic kidney disease.

Topics: Albuminuria; Animals; Antioxidants; Cell Line; Doxorubicin; Female; Glucosides; Heme Oxygenase-1; Hypercholesterolemia; Kelch-Like ECH-Associated Protein 1; Kidney; Lipid Peroxidation; Mice; Mice, Inbred BALB C; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Polygonum; RNA Interference; RNA, Small Interfering; Stilbenes

2,3,5,4'-Tetrahydroxystilbene-2-O-β-d-glucoside (TSG), an active component from the functional and medicinal herb Polygonum multiflorum Thunb, has the capacity of blocking angiotensin II (ANG II) signaling, a pathway within the renin-angiotensin system (RAS) which plays a critical role in the development of diabetic nephropathy (DN), and blockade of the RAS is currently used for the treatment of DN. Here we investigated the beneficial effect of TSG therapy on renal damage in the streptozotocin (STZ)-induced diabetes model. The STZ-treated C57BL/6J diabetic mice developed progressive albuminuria and renal tubular interstitial fibrosis within 10 weeks, accompanied by increased production of ANG II, fibronection, TGF-β, CTGF, TNF-α, RANTES and MCP-1 and decreased expression of slit diaphragm proteins in the kidney. The treatment of the diabetic mice with a TSG ameliorated kidney mass increase prevented albuminuria, and reduced tubular interstitial fibrosis. The TSG treatment suppressed the induction of fibronection, CTGF, TGF-β, and MCP-1 and reversed the decline of slit diaphragm proteins Neph-1, ZO-1, and FAT-1. These were accompanied by blockade of renal renin and ANG II accumulation induced by hyperglycemia. These data demonstrated that the inhibition of the RAS with TSG effectively prevented renal injury in diabetic nephropathy.

Topics: Albuminuria; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Gene Expression Regulation; Glucosides; Kidney; Male; Mice; Mice, Inbred C57BL; RNA, Messenger; Stilbenes