Protective effects of leflunomide on renal lesions in a rat model if diabetic nephropathy

Diabetic nephropathy is one of the most common chronic complications of diabetes with poor efficacy of clinical treatment. This study investigated the protective effects of leflunomide, a new immunosuppressant, on tubulointerstitial lesions in a rat model of diabetic nephropathy. Diabetes was induced with streptozotocin (STZ, 50mg/kg) by intraperitoneal injection in male Wistar rats. Two weeks after STZ injection, diabetic rats were treated daily for 8 weeks with low (5mg/kg) and high dose (10mg/kg) of leflunomide, and benazepril hydrochloride (4mg/kg) as a positive control. In diabetic rats, the 24-h urine volume, urine protein and microalbumin, blood creatinine and urea nitrogen significantly increased, which were attenuated by leflunomide treatment in a dose-dependent manner (all p<0.05). The increase of kidney weight/body weight and the histopathological findings of tubulointerstitial lesion in diabetic rats were mitigated by leflunomide treatment. Immunohistochemistry study and real-time polymerase chain reaction results demonstrated that osteopontin (OPN), transforming growth factor beta 1 (TGF-1), -smooth muscle actin and CD68 expression in the renal tubulointerstitial region were significantly increased in the diabetic rats, while these increases were inhibited by leflunomide treatment. These findings suggest that leflunomide protects the kidney injury of diabetic rats might through its inhibition of OPN/TGF-1 mediated extracellular matrix deposition and tubulointerstitial fibrosis, as well as its inhibition on tubular epithelial-myofibroblast transdifferentiation.