Beneficial Effect of Rhein on the Treatment of Diabetic Nephropathy in Nonobese Diabetic (NOD) Mice

Abstract

Objective: Rhein has been discovered early to have the function of inhibiting both electron transfer and ADP- driven H + uptake in mitochondria. It has been also found that rhein can inhibit the up regulation of GLUT1 (glucose transporting protein-1) function and the activity of hexosamine biosynthetic pathway in mesangial cells in vitro. Futhermore, we have showed the renal protective effect of rhein on STZ-induced diabetic rats. So we try to explore the therapeutic effects of rhein on diabetic nephropathy (DN) in another diabetic model of NOD mice. Methods: In our study, NOD mice of eight weeks of age were injected intraperitoneally four times with STZ (50 mg/kg) at 7-day interval. Mice with glycosuria and plasma glucose level above 14.0 mmol/L were verified for diabetes. Diabetic NOD mice were subdivided into control and rhein treatment groups. Mice in rhein treatment group were continuously administraed with rhein (150 mg/kg/d) for 15 weeks after diabetes was developed. Plasma parameters (including plasma glucose and lipid level), urinary protein level and histopathology of kidneys were all observed at the end of the experiment. Results: We demonstrate that rhein not only reduced the urinary protein excretion (0.37 ± 0.17 vs 3.32 ± 0.68 mg/24h, P<0.05), but also prevent the elevation of serum creatinine in diabetic mice after treatment of 15 weeks. In addition, rhein led to a marked decrease of plasma glucose level in experimental model, this effect reached its peak at 15 weeks (7.8 ± 3.80 vs 31.9 ± 4.77 mmol/L, P<0.01), accompanied with decrease of plasma triglyceride (0.74 ± 0.13 vs 2.16 ± 0.73 mmol/L, P<0.01) and cholesterols (1.84 ± 0.55 vs 6.53 ± 5.27 mmol/L, P<0.01). The morphologic studies showed the diabetic NOD mice present glomerular hypertrophy, mesangial expansion and diffuse sclerosis. The accumulation of fibronectin and deposition of immunoglobulin examined by immunostaining in glomeruli were found decreased in rhein-treated NOD mice. Examinition of pancreatic islet sections from NOD mice revealed peri-islet and intraislet mononuclear cells filtration. Treatment with rhein ameliorated cellular aggregation. Stain with Gomori aldehyde fuchsine method showed that loss of β-cells was reduced in rhein-treated mice. Conclusions: Taken together, these results indicate that rhein is able to ameliorate hyperglycemia and halt the progression of diabetic nephropathy in NOD mice, which possesses potential foreground on the management of human diabetes and its complications.