Mycophenolate Mofetil Prevents the Development of Glomerular Injury in Experimental Diabetes

Background: Experimental and clinical evidence suggests that inflammation plays a role in the pathogenesis of diabetic nephropathy, in addition to, or in concert with, the associated hemodynamic and metabolic changes. The present study assessed the effects of chronic anti-inflammatory therapy in experimental diabetic nephropathy.

Methods: Adult male Munich-Wistar rats were made diabetic with streptozotocin after uninephrectomy, kept moderately hyperglycemic by daily injections of NPH insulin and distributed among three groups: C, non-diabetic rats; DM, rats made diabetic and treated with insulin as described earlier; and DM+MMF, diabetic rats receiving insulin and treated with mycophenolate mofetil (MMF), 10 mg/kg once daily by gavage. Renal hemodynamic studies were performed 6 to 8 weeks after induction of diabetes. Additional rats were followed during 8 months, at the end of which renal morphological studies were performed.

Results: After 6 to 8 weeks, diabetic rats exhibited marked glomerular hyperfiltration and hypertension. Diabetic rats developed progressive albuminuria and exhibited widespread glomerulosclerotic lesions associated with macrophage infiltration at 8 months. Treatment with MMF had no effect on blood pressure, glomerular dynamics or blood glucose levels, but did prevent albuminuria, glomerular macrophage infiltration and glomerulosclerosis. Thus, the renoprotective effect of MMF was not associated with a metabolic or renal hemodynamic effect, and must have derived from its well-known anti-inflammatory properties, which include restriction of lymphocyte and macrophage proliferation and limitation of the expression of adhesion molecules.

Conclusions: These findings are consistent with the notion that inflammatory events are central to the pathogenesis of diabetic nephropathy and suggest that MMF may help prevent the progression of diabetic nephropathy.