Zhang Z et al. (2008) Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: blockade of compensatory renin increase. Proc Natl Acad Sci USA 105: 15896–15901

Renin–angiotensin system blockers are widely used to treat diabetic nephropathy, but compensatory renin release reduces their efficacy. Since vitamin D is known to repress renin gene transcription, Zhang et al. investigated whether combining a vitamin D analog (paricalcitol) and an angiotensin receptor blocker (losartan) leads to more effective inhibition of the renin–angiotensin system and prevention of renal injury in a mouse model of diabetic nephropathy.

Streptozotocin was used to induce diabetes in 8-week-old mice. At 2 weeks after streptozotocin injection, mice were randomly allocated to receive treatment with vehicle, losartan, paricalcitol or to a combination of losartan and paricalcitol. Vehicle-treated mice developed progressive albuminuria, with an almost fourfold increase in urinary albumin-to-creatinine ratio at 13 weeks. Although the development of albuminuria was ameliorated in mice receiving losartan or paricalcitol, the combination of losartan and paricalcitol prevented albuminuria completely; mice receiving combination therapy had a urinary albumin-to-creatinine ratio similar to that of untreated nondiabetic controls after 5 weeks and 10 weeks of treatment. In addition, combination therapy with losartan and paricalcitol prevented thickening of the glomerular basement membrane, prevented podocyte foot process effacement, reduced glomerulosclerosis, and suppressed induction of factors such as transforming growth factor β, which is implicated in the development of glomerulosclerosis.

These promising findings in a mouse model of diabetes might have important implications for the treatment of diabetic nephropathy in humans. The heightened therapeutic effects of the combination treatment are attributed to the suppression of renin and angiotensin II accumulation in the kidney.