The effect of angiotensin II receptor blockade on an end-stage renal failure model of type 2 diabetes.
The effect of olmesartan medoxomil (OLM), an angiotensin II receptor blocker (ARB), on advanced nephropathy and mortality was evaluated in Zucker Diabetic Fatty (ZDF) rats, a type 2 diabetes model. OLM was administered from 36 weeks of age, when the animals developed advanced proteinuria. OLM effectively suppressed the progression of proteinuria. The ZDF rats started to die at 50 weeks of age, which was accompanied by abrupt increase in blood urea nitrogen, suggesting that the cause of death was renal insufficiency. OLM suppressed increases in blood urea nitrogen and increased the survival rate of the ZDF rats. The histological examination revealed that the renal damage was ameliorated by OLM. The macrophage infiltration and monocyte chemoattractant protein-1 (MCP-1) expression was increased in the glomeruli and tubulointerstitium of the ZDF rat kidneys, and the increase was lessened by OLM. In a separate study, albumin increased MCP-1 release from cultured tubular epithelial cells. These results suggest that protein leakage from the glomeruli stimulates MCP-1 production in tubular cells and that MCP-1 released into the interstitial space induces macrophage infiltration and inflammation. It is conceivable that the beneficial actions of ARB on diabetic nephropathy are, at least in part, due to decrease of proteinuria and the subsequent reduction of inflammatory changes in tubular cells.
Mizuno
Makoto
M
Pharmacodymanics Research Laboratories, the Pharmacology and Molecular Biology Research Laboratories, and R&D Headquarters, Sankyo Co. Ltd., Tokyo, Japan.
Sada
Toshio
T
Kato
Mikio
M
Fukushima
Yasuo
Y
Terashima
Hideki
H
Koike
Hiroyuki
H
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D007093:Imidazoles / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007676:Kidney Failure, Chronic / Q000188:drug therapy*; D008055:Lipids / Q000097:blood; D008297:Male; D000068557:Olmesartan Medoxomil; D011507:Proteinuria / Q000188:drug therapy; D051381:Rats; D012709:Serum Albumin / Q000032:analysis; D015996:Survival Rate; D013599:Systole / Q000187:drug effects; D013777:Tetrazoles / Q000627:therapeutic use*
D047228:Angiotensin II Type 1 Receptor Blockers; D001786:Blood Glucose; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D007093:Imidazoles; D008055:Lipids; D012709:Serum Albumin; D013777:Tetrazoles; D000068557:Olmesartan Medoxomil; D003404:Creatinine