Nipradilol prevents L-NAME-exacerbated nephrosclerosis with decreasing of caspase-3 expression in SHR.
The proliferative cell nuclear antigen (PCNA) is an auxiliary protein of DNA polymerase delta and appears to be required for both DNA synthesis and repair. Previously, we showed that prolonged NO synthase (NOS) inhibition produced severe nephrosclerosis with an increase of glomerular cell DNA fragmentation (apoptosis), glomerular ischemia and hypertension in spontaneously hypertensive rats (SHR). The objective of the present study was to investigate the effects of the vasodilating, nonselective, NO-releasing beta-adrenoceptor blocker nipradilol on DNA fragmentation and synthesis/repair of glomerular cells in this prolonged NOS blockaded SHR. Twenty-week-old SHR were administered an NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 80 mg/l in drinking water) or co-treated with the same dose of L-NAME and nipradilol (20 mg/kg/day) for 3 weeks. After this treatment, expression of apoptosis was histologically examined using caspase-3, an apoptosis inducer, in addition PCNA (DNA synthesis/repair), and examination of glomerular morphometric changes, including cell number and tuft area. Nipradilol reduced blood pressure and preserved creatinine clearance reduction in L-NAME/SHR. These effects were associated with normalization of the glomerular cell apoptosis index and caspase-3 score, an increase in PCNA index, and increases in glomerular cell numbers and glomerular tuft area, resulting in a decreased glomerular injury score. Thus, in SHR administered an NOS inhibitor, nipradilol improved nephrosclerosis in association with a decrease in apoptosis and an increase in DNA synthesis/repair of glomerular cells. These findings may provide important insights into DNA repair/repair and apoptosis in nephrosclerosis.
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Tochigi, Japan.
Hideki
H
Inada
Hidehiko
H
Ono
Junichi
J
Minami
Toshihiko
T
Ishimitsu
Hiroaki
H
Matsuoka
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis*; D006973:Hypertension / Q000150:complications / Q000188:drug therapy*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity*; D009400:Nephrosclerosis / Q000517:prevention & control*; D009569:Nitric Oxide / Q000096:biosynthesis; D009929:Organ Size / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar
D000319:Adrenergic beta-Antagonists; D018809:Proliferating Cell Nuclear Antigen; D011412:Propanolamines; D009569:Nitric Oxide; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C036089:nipradilol; D019331:NG-Nitroarginine Methyl Ester