Sugaru Eiji, Nakagawa Tsutomu, Ono-Kishino Michiko, Nagamine Jun, Tokunaga Teruhisa, Kitoh Makoto, Hume W Ewan, Nagata Ryu, Taiji Mutsuo
Dainippon Sumitomo Pharma Co., Ltd., Drug Research Division, Pharmacology Research Laboratories, Kasugadenaka, Osaka, Japan.
Am J Nephrol. 2006;26(1):50-8. doi: 10.1159/000091786. Epub 2006 Feb 24.
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-beta 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.
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.
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.
A combination of the two agents, SMP-534 and losartan, might be a valuable therapeutic approach for the treatment of diabetic nephropathy.
背景/目的：糖尿病肾病现已成为终末期肾病最常见的病因。同样明确的是，目前的治疗方法，即血管紧张素II阻断，无法阻止糖尿病肾病的进展。我们之前已经证明，一种抗纤维化药物SMP - 534在体外可减少转化生长因子 - β诱导的细胞外基质生成，并且SMP - 534通过非降压机制预防糖尿病db/db小鼠的肾纤维化和尿白蛋白。我们预期联合使用SMP - 534和氯沙坦会产生更强的肾脏保护作用。
我们研究了SMP - 534与氯沙坦联合治疗对db/db小鼠尿白蛋白和肾小球纤维化的影响。从9周龄到25周龄为小鼠提供含这些药物的饮食。在第8、17和25周进行血液和尿液分析。在研究结束时，对肾脏组织进行组织学分析。
SMP - 534显著抑制db/db小鼠尿白蛋白排泄增加，并改善肾小球纤维化进展，而氯沙坦则无此作用。与单独使用SMP - 534或氯沙坦治疗相比，SMP - 534与氯沙坦联合治疗显著预防了尿白蛋白排泄增加。相比之下，肾脏组织学分析显示，与单独使用SMP - 534治疗相比，联合治疗并未显著预防肾脏系膜扩张增加。
SMP - 534和氯沙坦这两种药物联合使用可能是治疗糖尿病肾病的一种有价值的治疗方法。
