Efficacy of Aliskiren, Compared with Angiotensin II Blockade, in Slowing the Progression of Diabetic Nephropathy in Db/db Mice: Should the Combination Therapy Be a Focus?

Although the intensive use of angiotensin II blockade (ACEI or ARB), progression of diabetic nephropathy is common. A feedback increase in renin production often accompanies angiotensin II blockade. We therefore examined whether aliskiren, a direct renin inhibitor, confers better renoprotection than angiotensin II blockade and whether the addition of aliskiren to an ACEI or ARB would enhance the efficacy in slowing the progression of glomerulosclerosis in diabetes. Untreated db/db mice developed progressive mesangial matrix expansion and albuminuria between weeks 18 and 22, associated with reduction of WT-1 immunopositive podocytes and nephrin and podocin production and induction of desmin and B7-1 generation and renal expression of TGFß1, PAI-1, fibronectin and type IV collagen. Treatment with aliskiren at 30 mg/kg/d inhibited the increases in albuminuria and markers of renal fibrosis and the changes that are indicative of podocyte injury seen in the db/db mice. Notably, the therapeutic effect of aliskiren was similar to that of either enalapril or valsartan given alone at maximally effective doses. Combined therapy caused the loss of 10% ~ 16.6% of db/db mice, yielded no further reduction in renal fibrosis and podocyte injury but further reduced albuminuria and renal production of TNFα, Nox2 and p47phox and urine MCP-1 and malondialdehyde levels, the markers of renal inflammation and oxidative stress. These results suggest that aliskiren, enalapril and valsartan are equally effective in slowing the progression of diabetic nephropathy. The use of combination therapy with aliskiren and ACEI/ARB may not be strongly supported.