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

Vol. 26, No. 1, 2006

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Original Report: Laboratory Investigation

Enhanced Effect of Combined Treatment with SMP-534 (Antifibrotic Agent) and Losartan in Diabetic Nephropathy
Eiji Sugaru^a, Tsutomu Nakagawa^a, Michiko Ono-Kishino^a, Jun Nagamine^a, Teruhisa Tokunaga^b, Makoto Kitoh^c, W. Ewan Hume^b, Ryu Nagata^b, Mutsuo Taiji^a

Dainippon Sumitomo Pharma Co., Ltd., Drug Research Division,
^aPharmacology Research Laboratories,
^bChemistry Research Laboratories,
^cTechnology Research and Development Center, Chemical Synthesis Laboratories, Osaka, Japan

Address of Corresponding Author

Am J Nephrol 2006;26:50-58 (DOI: 10.1159/000091786)

Key Words

Diabetic nephropathy
Fibrosis
Losartan
Urinary albumin

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- 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. 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.

Author Contacts

Mutsuo Taiji, PhD
Dainippon Sumitomo Pharma Co., Ltd., Drug Research Division
Pharmacology Research Laboratories, Discovery Pharmacology Group I
3-1-98 Kasugadenaka, Konohana-ku, Osaka 554-0022 (Japan)
Tel. +81 6 6466 5264, Fax +81 6 6466 5182, E-Mail mutsuo-taiji@ds-pharma.co.jp

Article Information

Received: September 30, 2005
Accepted: December 29, 2005
Published online: February 24, 2006
Number of Print Pages : 9
Number of Figures : 5, Number of Tables : 1, Number of References : 46

Medline Abstract (ID 16508247)

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