Imidapril improves L-NAME-exacerbated nephrosclerosis with TGF-beta 1 inhibition in spontaneously hypertensive rats.
OBJECTIVE
This study was designed to investigate whether chronic angiotensin-converting enzyme (ACE) inhibition prevents hypertensive glomerular injury and inhibits increases in the mRNA levels and immunohistological expression of the apoptosis inducer caspase-3, and transforming growth factor (TGF)-beta 1 during prolonged nitric oxide synthase (NOS) inhibition with N-nitro-L-arginine methyl ester (L-NAME) in spontaneously hypertensive rats (SHR).


RESULTS
For 3 weeks, we studied three groups of 20-week-old male SHR: a control group, a l-NAME group, and a group treated with L-NAME and the ACE inhibitor imidapril. L-NAME rats developed severe hypertensive nephrosclerosis with significantly elevated blood pressure, markedly increased urinary protein excretion and serum creatinine levels, and more severe glomerulosclerosis and tubulo-interstitial changes. Levels of TGF-beta 1 mRNA in the renal tissue was also significantly increased in L-NAME rats compared with control SHR. Addition of imidapril significantly lowered blood pressure, inhibited nephrosclerosis and attenuated the mRNA level of TGF-beta 1 in comparison with L-NAME/SHR. Histologically, the glomerular cell apoptosis labeling index, terminal doxynucleotidil transferase-mediated dUTP nick-end labeling of fragmented DNA (TUNEL) and active caspase-3, and TGF-beta 1 positive areas were also reduced by imidapril.


CONCLUSIONS
These data suggest that imidapril prevents glomerular and arteriolar damages and renal functions, through inhibiting both TGF-beta 1 production and apoptosis induction.
Ono
Hidehiko
H
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Shimotsuga, Tochigi, Japan. onoh@dokkyomed.ac.jp
Saitoh
Mayumi
M
Ono
Yuko
Y
Ishimitu
Toshihiko
T
Matsuoka
Hiroaki
H
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000473:pathology; D006332:Cardiomegaly / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000473:pathology; D048289:Imidazolidines / Q000494:pharmacology*; D007668:Kidney / Q000473:pathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009400:Nephrosclerosis / Q000139:chemically induced / Q000473:pathology*; D009929:Organ Size; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics; D053773:Transforming Growth Factor beta1
D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D048289:Imidazolidines; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C065166:imidapril; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D019331:NG-Nitroarginine Methyl Ester