Amelioration of established diabetic nephropathy by combined treatment with SMP-534 (antifibrotic agent) and losartan in db/db mice.

Abstract

BACKGROUND/AIMS: Diabetic nephropathy is the main cause of end-stage renal disease. Previously we have demonstrated that SMP-534 (an antifibrotic agent) prevents the development of diabetic nephropathy in db/db mouse and that combined treatment with SMP-534 and losartan (antihypertensive agents) markedly prevents the development of diabetic nephropathy compared with single treatment. SMP-534 or losartan was prophylactically administered to db/db mice before the onset of diabetic nephropathy. In the present study, we evaluated the efficacy of combined treatment when administration was started after the onset of diabetic nephropathy. METHODS: db/db mice were raised untreated until 17 weeks of age, by which time increase of urinary albumin was noted, and then treated with SMP-534 and/or losartan for another 8 weeks. Biochemical and histological analyses were performed at 25 weeks of age. RESULTS: Combined treatment with SMP-534 and losartan markedly prevented the increase of urinary albumin and ameliorated the progression of mesangial matrix expansion, even when administration was started long after the increase of urinary albumin. CONCLUSION: The study results indicate that a combination of SMP-534 and losartan might be a valuable therapeutic approach for the treatment of diabetic nephropathy even when administration is started after the onset of diabetic nephropathy.