dihydropyridines and Glomerulosclerosis--Focal-Segmental

Angiotensin receptor blockers (ARBs) or T- and L-type calcium channel blockers (CCBs) are useful for glomerular protection; however, the protective effects of combination therapy remain unclear. In this study, Dahl salt-sensitive rats were fed a high-salt diet and were treated daily with placebo, irbesartan (60 mg kg(-1)), efonidipine (30 mg kg(-1)), irbesartan (60 mg kg(-1))+efonidipine (30 mg kg(-1)), amlodipine (3 mg kg(-1)), or irbesartan (60 mg kg(-1))+amlodipine (3 mg kg(-1)) for 4 weeks. Significant reductions in systolic blood pressure were seen in the irbesartan-, efonidipine- and amlodipine-treated groups compared with the placebo-treated group; a further significant reduction was seen in the irbesartan+efonidipine-treated group compared with the irbesartan-treated group. Compared with the placebo-treated group, proteinuria was significantly lower in the irbesartan- and efonidipine-treated groups, but not in the amlodipine-treated group. Furthermore, a significant attenuation of proteinuria in the irbesartan+efonidipine-treated group compared with the irbesartan-treated group was observed; this effect was not observed in the irbesartan+amlodipine-treated group. The glomerulosclerosis index was significantly attenuated by all active treatments except amlodipine. The glomerulosclerosis index in the irbesartan+efonidipine-treated group, but not in the irbesartan+amlodipine-treated group, was significantly lower than that in the irbesartan-treated group. Significant attenuations of gene expressions of p22(phox), transforming growth factor-beta, monocyte chemoattractant protein-1 and collegen I were observed in the irbesartan- and efonidipine-treated groups, but not in the amlodipine-treated group. Values for these parameters were reduced to control levels in the irbesartan+efonidipine-treated group. Combination therapy with ARB and T- and L-type CCB might produce a powerful renal protective effect.

Topics: Amlodipine; Angiotensin II Type 1 Receptor Blockers; Animals; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Chemokine CCL2; Collagen Type I; Dihydropyridines; Drug Therapy, Combination; Gene Expression; Glomerulosclerosis, Focal Segmental; Hypertension; Irbesartan; Kidney Glomerulus; Male; NADPH Oxidases; Nitrophenols; Organophosphorus Compounds; Proteinuria; Rats; Rats, Inbred Dahl; Tetrazoles; Transforming Growth Factor beta

Recent studies on various models of glomerular diseases indicate that glomerular injury is associated with the phenotypic modulation of glomerular cells. However, the effect of renoprotective agents on glomerular phenotype remains to be determined. This study examined the effects of angiotensin II Type 1 (AT1) receptor antagonists and calcium antagonists on glomerular phenotypic changes in rats with subtotal renal ablation. Rats were subjected to 5/6 nephrectomy and were given oral TCV-116, a selective AT1 receptor antagonist (1 mg/kg), manidipine, a dihydropyridine calcium antagonist (3 mg/kg), or vehicle for 8 wk. Glomerular phenotypic modulation was determined by the staining of alpha-smooth muscle actin and desmin in glomerular cells with an immunohistochemical technique. At the start of drug treatment, alpha-smooth muscle actin and desmin were already significantly expressed in the glomerular cells of 5/6-nephrectomized rats, in contrast to a negligible glomerular expression of these proteins in sham-operated rats. Treatment of 5/6-nephrectomized rats with TCV-116 or manidipine significantly decreased glomerular expression of alpha-smooth muscle actin and desmin, thereby indicating that these drugs prevented glomerular phenotypic changes in 5/6-nephrectomized rats. Furthermore, their inhibitory effects on glomerular phenotypic modulation were associated with the prevention of glomerular cell proliferation, hypertrophy, and sclerosis. Therefore, this study provides the first evidence that the renoprotection is linked to the prevention of glomerular phenotypic modulation and supports the idea that this phenotypic modulation may serve as an important cellular marker of glomerular injury.

Topics: Actins; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biomarkers; Biphenyl Compounds; Blood Pressure; Blood Urea Nitrogen; Calcium Channel Blockers; Desmin; Dihydropyridines; Drug Synergism; Drug Therapy, Combination; Extracellular Matrix; Glomerulosclerosis, Focal Segmental; Kidney; Kidney Glomerulus; Male; Metabolic Clearance Rate; Nephrectomy; Nitrobenzenes; Organ Size; Phenotype; Piperazines; Rats; Rats, Sprague-Dawley; Tetrazoles

The effects of calcium antagonism on the development and progression of renal disease are controversial. To address this problem, studies were performed on young, uninephrectomized spontaneously hypertensive rats (SHRs) with the dihydropyridine calcium antagonist, manidipine, to assess its effect on the early pathogenesis of focal glomerulosclerosis. Male SHRs underwent uninephrectomy at age 10 to 11 weeks and were subsequently assigned to no treatment (control), a predetermined subvasodepressor (low) dose of manidipine (2.5 mg/kg body weight), or a predetermined antihypertensive (high) dose of manidipine (20 mg/kg body weight). All animals received a diet containing 0.4% sodium and 23% protein. Serial determinations of body weight, systolic tail cuff pressure, and 24-hour urinary excretion of creatinine, sodium, and protein (UprotV) were made at 1- to 6-week intervals, for a total treatment period of 12 weeks. In final experiments plasma was obtained for creatinine, angiotensin I, and angiotensin II determinations, and renal tissue was harvested for histologic and morphometric analysis. Compared with the untreated control, low-dose manidipine therapy had no effect on body weight, systolic blood pressure, creatinine clearance, UprotV, renal histologic findings, glomerular volume, or plasma angiotensin I or II concentrations. In contrast, high-dose manidipine therapy decreased systolic blood pressure from 194 +/- 3 to 160 +/- 4 mm Hg (p < 0.01). Creatinine clearance and UprotV were unchanged. Although body weight was not different, kidney weight was higher. However, mean glomerular volume was lower. More importantly, the prevalence of mesangial expansion with proliferation was lower: 6.7% (control) versus 2.8% (high-dose manidipine) (p < 0.01). Finally, plasma angiotensin I and angiotensin II concentrations did not differ.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin II; Animals; Calcium Channel Blockers; Dihydropyridines; Glomerular Mesangium; Glomerulosclerosis, Focal Segmental; Kidney; Male; Nephrectomy; Nitrobenzenes; Piperazines; Proteinuria; Rats; Rats, Inbred SHR

An experimental focal segmental glomerular sclerosis (FSGS) was induced by the combined administration of puromycin aminonucleoside (PAN) and protamine sulfate (PS). Blood collections were made on days 0, 37, 70 and 94. Urine collections were made on days 0, 24, 80 and 94. Vehicle-treated rats showed severe proteinuria and an increase in serum total cholesterol (sTC). Benidipine (1 or 3 mg/kg, p.o.)-treated rats exhibited less proteinuria and lower sTC than the vehicle-treated rats. On days 70 and 94, both blood urea nitrogen (BUN) and serum creatinine (sCR) values in the vehicle-treated rats were significantly higher than those in normal rats (without treatment with PAN and PS). On the other hand, the treatment with benidipine (1 or 3 mg/kg, p.o.) attenuated the increases in BUN and sCR. On day 94, vehicle-treated rats showed a significant decrease in creatinine clearance as compared with normal rats, but benidipine (1 or 3 mg/kg, p.o.)-treated rats did not. The histology was examined on day 94. Vehicle-treated rats demonstrated a significantly greater percentage of glomeruli with segmental areas of glomerulosclerosis/hyalinosis, mesangial cell proliferation, and mesangial foam cell. Benidipine (3 mg/kg, p.o.) ameliorated the development of renal regeneration as estimated by histological examination. These results suggest that the Ca-channel blocker benidipine is a favorable drug for preventing the progression of glomerular sclerosis.

Topics: Animals; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Glomerulosclerosis, Focal Segmental; Kidney; Male; Nephrotic Syndrome; Protamines; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley; Urine