Prevention of cardiovascular and renal pathology of aging by the advanced glycation inhibitor aminoguanidine.
Human aging is impacted severely by cardiovascular disease and significantly but less overtly by renal dysfunction. Advanced glycation endproducts (AGEs) have been linked to tissue damage in diabetes and aging, and the AGE inhibitor aminoguanidine (AG) has been shown to inhibit renal and vascular pathology in diabetic animals. In the present study, the effects of AG on aging-related renal and vascular changes and AGE accumulation were studied in nondiabetic female Sprague-Dawley (S-D) and Fischer 344 (F344) rats treated with AG (0.1% in drinking water) for 18 mo. Significant increases in the AGE content in aged cardiac (P < 0.05), aortic (P < 0.005), and renal (P < 0.05) tissues were prevented by AG treatment (P < 0.05 for each tissue). A marked age-linked vasodilatory impairment in response to acetylcholine and nitroglycerine was prevented by AG treatment (P < 0.005), as was an age-related cardiac hypertrophy evident in both strains (P < 0.05). While creatinine clearance was unaffected by aging in these studies, the AGE/ creatinine clearance ratio declined 3-fold in old rats vs. young rats (S-D, P < 0.05; F344, P < 0.01), while it declined significantly less in AG-treated old rats (P < 0.05). In S-D but not in F344 rats, a significant (P < 0.05) age-linked 24% nephron loss was completely prevented by AG treatment, and glomerular sclerosis was markedly suppressed (P < 0.01). Age-related albuminuria and proteinuria were markedly inhibited by AG in both strains (S-D, P < 0.01; F344, P < 0.01). These data suggest that early interference with AGE accumulation by AG treatment may impart significant protection against the progressive cardiovascular and renal decline afflicting the last decades of life.
Li
Y M
YM
Picower Institute for Medical Research, Manhasset, NY 11030, USA.
Steffes
M
M
Donnelly
T
T
Liu
C
C
Fuh
H
H
Basgen
J
J
Bucala
R
R
Vlassara
H
H
D000109:Acetylcholine / Q000494:pharmacology; D000375:Aging / Q000502:physiology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D006332:Cardiomegaly / Q000503:physiopathology / Q000517:prevention & control; D003404:Creatinine / Q000097:blood / Q000652:urine; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000254:growth & development*; D007668:Kidney / Q000187:drug effects / Q000254:growth & development / Q000473:pathology*; D024510:Muscle Development; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000254:growth & development / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D005996:Nitroglycerin / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D011507:Proteinuria; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014664:Vasodilation / Q000187:drug effects
D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006146:Guanidines; D003404:Creatinine; D005996:Nitroglycerin; D000109:Acetylcholine; C004479:pimagedine