Enhanced Effect of Combined Treatment with SMP-534 (Antifibrotic Agent) and Losartan in Diabetic Nephropathy

Abstract

Background/Aims: Diabetic nephropathy is now the most common cause of end-stage renal disease. It is also clear that the current therapy, angiotensin II blockage, cannot prevent the progression of diabetic nephropathy. We had previously demonstrated that an antifibrotic agent, SMP-534, reduced extracellular matrix production induced by transforming growth factor-β in vitro, and that SMP-534 prevented renal fibrosis and urinary albumin in diabetic db/db mice via a nonantihypertensive mechanism. We expected that combined use of SMP-534 and losartan would produce a more highly renoprotective action. Methods: We examined the effects of combined treatment with SMP-534 and losartan on urinary albumin and glomerular fibrosis in db/db mice. Diet containing these agents was provided from age 9 to 25 weeks. Blood and urine analyses were performed at 8, 17, and 25 weeks. At the end of the study, kidney tissues were histologically analyzed. Results: SMP-534 significantly suppressed an increase in urinary albumin excretion and ameliorated the progression of glomerular fibrosis in db/db mice, whereas losartan did not. Combined treatment with SMP-534 and losartan markedly prevented the increase of urinary albumin excretion compared with treatment with either SMP-534 or losartan alone. In contrast, renal histological analysis revealed that combined treatment did not significantly prevent an increase of mesangial expansion in the kidney compared with treatment with SMP-534 alone. Conclusion: A combination of the two agents, SMP-534 and losartan, might be a valuable therapeutic approach for the treatment of diabetic nephropathy.

Amelioration of Established Diabetic Nephropathy by Combined Treatment with SMP-534 (Antifibrotic Agent) and Losartan in <i>db/db</i> Mice

“…We have discovered SMP-534, which inhibits ECM production induced by TGF-β [12], and reported that SMP-534 shows a renoprotective effect in db/db mice independent of the hypoglycemic or antihypertensive effect [13]. Additionally, we reported that the combination of SMP-534 and losartan exerted a renoprotective effect superior to single use because of differences in the mechanism of action [14]. In these studies, we started SMP-534 administration concurrently with the onset of diabetes, demonstrating the efficacy of SMP-534 in preventing diabetic nephropathy.…”

“…We have also demonstrated that SMP-534 prevents the progression of renal lesions in db/db mice [13] and that combined treatment of SMP-534 and losartan, an antihypertensive agent, prevents the progression of renal lesions in db/db mice more significantly than singular treatment with SMP-534 or losartan [14]. However, in our previous experiments, SMP-534 treatment was started concomitantly with the onset of diabetes, demonstrating the efficacy of SMP-534 treatment in preventing diabetic nephropathy.…”

Immunoinflammation in Diabetic Nephropathy: Molecular Mechanisms and Therapeutic Options

“…In diabetic patients, treatment with the ACE inhibitor perindopril reduced the intrarenal TGF-expression and activity (Langham et al, 2006). Furthermore, the antifibrotic agent N-acetyl-serylaspartyl-lysyl-proline, which reduced TGF--induced extracellular matrix production and prevented renal fibrosis and albuminuria in diabetic db/db mice, conferred an additional renoprotective effect when combined with the angiotensin II receptor antagonist losartan (Sugaru et al, 2006).…”

Drugs for Diabetic Nephropathy- Full Review

“…[95] Drugs that modify TGFβ expression or reduce TGFβ level 1) ACE inhibitor Perindopril reduces intrarenal TGFβ expression and activity [125] 2) ACE inhibitor reduces serum and urinary level of TGFβ [131] 3) Antifibrotic agent N-acetyl-seryl-aspartyl-lysyl-proline reduced extracellular matrix production, prevented fibrosis and albuminuria in mice model. Also additional renoprotection can be offered when combined with angiotensin II receptor antagonist losartan [130,140] www.wjpps.com 2) Several blocking Abs against TGFβ reduce mesangial matrix accumulation and glomerulosclerosis in diabetic mouse model [75,132] 3) TGF-AY1Ab is in clinical development for the treatment of chronic kidney diseases with focus on diabetic nephropathy. [90] DRUGS-Pirfenidone [133] , Tranilast [134,135] , fresolimumab.…”