Activity of the Chinese prescription Hachimi-jio-gan against renal damage in the Otsuka Long-Evans Tokushima Fatty rat: a model of human type 2 diabetes mellitus

Abstract

Currently, in Japan, approximately 95% of patients with diabetes mellitus have non-insulin-dependent (type 2) diabetes mellitus (NIDDM), and diabetic nephropathy is a major cause of patients requiring chronic haemodialysis. A previous study showed that Hachimi-jio-gan has a protective effect in rats subjected to subtotal nephrectomy plus streptozotocin injection, a model of insulin-dependent (type 1) diabetic nephropathy. In this study, we used the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of human NIDDM, to investigate whether long-term administration of Hachimi-jio-gan affects glycaemic control and renal function in NIDDM. Male OLETF rats, aged 22 weeks, were divided into 4 groups of 10 and given Hachimi-jio-gan (50, 100 or 200 mg kg−1 daily) orally or no treatment for 32 weeks. Male Long-Evans Tokushima Otsuka (LETO) rats (n = 6) were used as non-diabetic normal controls. Hachimi-jio-gan reduced hyperglycaemia dose-dependently from 16 weeks of the administration period. Urinary protein excretion decreased significantly from an early stage, and creatinine clearance levels improved at 32 weeks. In addition, the levels of serum glycosylated protein and renal advanced glycation end-products were effectively reduced. Hachimi-jio-gan also significantly reduced the levels of thiobarbituric acid-reactive substances in renal mitochondria, although it showed only a tendency to reduce these in serum. Furthermore, long-term administration of Hachimi-jio-gan reduced renal cortical expression of proteins, such as transforming growth factor-β1 (TGF-β1), fibronectin, inducible nitric oxide synthase and cyclooxygenase-2. The 100- and 200-mg kg−1 daily doses of Hachimi-jio-gan significantly reduced TGF-β1 and fibronectin protein expression to levels below those of LETO rats. These data suggest that Hachimi-jio-gan may have a beneficial effect on the progression of diabetic nephropathy in OLETF rats by attenuating glucose toxicity and renal damage.