Benidipine, a long-acting calcium-channel blocker, prevents the progression to end-stage renal failure in a rat mesangioproliferative glomerulonephritis.
BACKGROUND
Although the renoprotective effect of calcium-channel blockers (CCBs) has been examined in several models of hypertensive nephropathy, it remains unclear. It also remains to be clarified whether CCBs prevent the progression to end-stage renal failure in chronic progressive glomerulonephritis (GN). A new rat model of progressive mesangioproliferative GN was used to study the effect of benidipine hydrochloride, a long-acting dihydropyridine CCB, on the clinical features and morphological lesions.


METHODS
This animal model of progressive GN was induced by a single intravenous injection of anti-Thy-1 monoclonal antibody (MoAb 1-22-3) two weeks after unilateral nephrectomy. After 10 weeks of treatment with benidipine (1, 3, and 5 mg/kg body weight, p.o.) or hydralazine (5 mg/kg body weight, p.o.), systolic blood pressure (SBP), urinary protein excretion, creatinine clearance, glomerulosclerosis index, tubulointerstitial lesion index, glomerular cross-sectional area, and glomerular expression of transforming growth factor-beta (TGF-beta) and alpha-smooth muscle actin (alpha-SMA) were measured.


RESULTS
Untreated rats developed hypertension, massive proteinuria, renal dysfunction, severe glomerular and tubulointerstitial injury, higher glomerular size, and marked glomerular staining for TGF-beta and alpha-SMA, while uninephrectomized control rats did not. Each dose of benidipine and hydralazine equally reduced SBP to uninephrectomized control levels. Three and five mg/kg/day of benidipine increased creatinine clearance, ameliorated glomerular and tubulointerstitial injury, and reduced glomerular staining for TGF-beta and alpha-SMA, but 1 mg/kg/day of benidipine and hydralazine failed. Only a dose of 5 mg/kg/day of benidipine reduced glomerular size, although it did not reduce the size to control levels.


CONCLUSIONS
These results indicate that in a rat model of progressive mesangioproliferative GN, benidipine prevents the progression to end-stage renal failure in a dose-dependent manner. This renoprotective action is associated with the suppression of glomerular expression of TGF-beta and alpha-SMA.
Nakamura
T
T
Division of Blood Transfusion, Yamanashi Medical University, Yamanashi, Japan.
Obata
J E
JE
Onitsuka
M
M
Shimada
Y
Y
Yoshida
Y
Y
Kawachi
H
H
Shimizu
F
F
D000199:Actins / Q000032:analysis; D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003404:Creatinine / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005455:Fluorescent Antibody Technique; D015432:Glomerulonephritis, Membranoproliferative / Q000188:drug therapy* / Q000473:pathology; D006830:Hydralazine / Q000494:pharmacology; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D007678:Kidney Glomerulus / Q000737:chemistry / Q000473:pathology; D008297:Male; D009392:Nephrectomy; D011507:Proteinuria / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000032:analysis; D014665:Vasodilator Agents / Q000494:pharmacology
D000199:Actins; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D016212:Transforming Growth Factor beta; D014665:Vasodilator Agents; D006830:Hydralazine; C061004:benidipine; D003404:Creatinine