Enhanced effect of combined treatment with SMP-534 (antifibrotic agent) and losartan in diabetic nephropathy.
OBJECTIVE
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.


CONCLUSIONS
A combination of the two agents, SMP-534 and losartan, might be a valuable therapeutic approach for the treatment of diabetic nephropathy.
Sugaru
Eiji
E
Dainippon Sumitomo Pharma Co., Ltd., Drug Research Division, Pharmacology Research Laboratories, Kasugadenaka, Osaka, Japan.
Nakagawa
Tsutomu
T
Ono-Kishino
Michiko
M
Nagamine
Jun
J
Tokunaga
Teruhisa
T
Kitoh
Makoto
M
Hume
W Ewan
WE
Nagata
Ryu
R
Taiji
Mutsuo
M
D000419:Albuminuria; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage*; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005355:Fibrosis / Q000188:drug therapy; D007668:Kidney / Q000473:pathology; D007678:Kidney Glomerulus / Q000473:pathology; D019808:Losartan / Q000008:administration & dosage*; D008297:Male; D051379:Mice
D047228:Angiotensin II Type 1 Receptor Blockers; D001549:Benzamides; C505358:SMP-534; D019808:Losartan