title: Anti-hypertensive agents inhibit in vivo the formation of advanced glycation end products and improve renal damage in a type 2 diabetic nephropathy rat model.
abstract: Prevention or retardation of diabetic nephropathy (DN) includes anti-hypertensive treatment with angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) on the premises that these drugs have an added protective effect beyond their influence on BP. The present study used a strain of spontaneously hypertensive/NIH-corpulent rats [SHR/NDmc-cp (fat/fat)] as a model of type II DN to unravel the renoprotective effects of anti-hypertensive drugs. Olmesartan (1 or 5 mg/kg per d), an ARB, and hydralazine (5mg/kg per d), an anti-hypertensive drug without effect on the renin-angiotensin system (RAS), were given for 20 wk. BP, renal function, glucose and insulin levels, and proteinuria were monitored. Glomerular lesions and kidney pentosidine content were assessed at the end of the study. Olmesartan (1 and 5 mg) significantly reduced BP and kidney pentosidine content and improved histologic renal damage and proteinuria. The changes were dose-dependent. The effect of hydralazine (5 mg) was similar to that of olmesartan (1 mg) but reached statistical significance only for kidney pentosidine content. The similarity of both drugs' effects on kidney damage and proteinuria suggest that renoprotection does not hinge on manipulation of RAS in these rats. By contrast, the inhibition of renal pentosidine formation assessed both by immunohistochemistry and HPLC suggests a critical role of advanced glycation end product (AGE) formation together with hypertension in the genesis of diabetic nephropathy. This view is supported by the correlation found between renal pentosidine content and proteinuria. The unsuspected AGE-lowering effect of hydralazine was further confirmed in vitro and elucidated; it is due to both reactive carbonyl compounds trapping and modifications of the oxidative metabolism. It is concluded that AGE inhibition should be included in the therapeutic strategy of DN.
authors.affiliation: Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan.
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.forename: Toshio
authors.initials: T
authors.lastname: Sada
authors.forename: Makoto
authors.initials: M
authors.lastname: Mizuno
authors.forename: Reiko
authors.initials: R
authors.lastname: Inagi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Ueda
authors.forename: Naoyoshi
authors.initials: N
authors.lastname: Ishikawa
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yuzawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koike
authors.forename: Charles
authors.initials: C
authors.lastname: van Ypersele de Strihou
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kurokawa
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives* / Q000032:analysis; D001786:Blood Glucose; D001794:Blood Pressure; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006830:Hydralazine / Q000494:pharmacology; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007668:Kidney / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008055:Lipids / Q000097:blood; D008239:Lysine / Q000031:analogs & derivatives* / Q000032:analysis; D008297:Male; D000068557:Olmesartan Medoxomil; D010084:Oxidation-Reduction; D011507:Proteinuria / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051381:Rats; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D001786:Blood Glucose; D017127:Glycation End Products, Advanced; D007093:Imidazoles; D008055:Lipids; D013777:Tetrazoles; D006830:Hydralazine; D000068557:Olmesartan Medoxomil; D001120:Arginine; C062187:pentosidine; D008239:Lysine