Effect of ramipril, nifedipine, and moxonidine on glomerular morphology and podocyte structure in experimental renal failure.
BACKGROUND
Experimental renal failure causes structural alterations of the kidney. It is still unresolved how these changes are modified by antihypertensive treatment. Purpose of the study. To examine the effects of different antihypertensive agents (ramipril, nifedipine, moxonidine) mainly on glomerular geometry, cell number, cell morphology, and capillarization, in a subtotal nephrectomy model of renal failure.


METHODS
Sham-operated male SD rats and subtotally nephrectomized (SNX) ad libitum-fed rats were examined. Groups of 8-10 SNX rats were left untreated or were treated with ramipril (0.5 mg/kg b.w. per day), nifedipine (20 mg/kg b.w. per day) or moxonidine (10 mg/kg b.w.per day) respectively. After perfusion fixation the kidneys were examined using stereological techniques.


RESULTS
Systolic blood pressure (by tail plethysmography) was 110+/-13 mm Hg in sham-op and 119+/-9 in SNX. It was effectively and comparably reduced below normal values by ramipril (89+/-11 mmHg), nifedipine (98+/-23 mmHg) and moxonidine (92+/-11 mmHg). The glomerulosclerosis index (SI) was significantly increased in SNX versus sham-op; it was similarly decreased by ramipril and moxonidine but less so by nifedipine. Vascular damage (preglomerular vessels) was reduced by all treatments whereas tubulointerstitial damage was signficantly reduced only by ramipril and moxonidine. Mean glomerular tuft volume was increased in SNX compared to sham-op. controls and was normalized only by ramipril treatment. Glomerular cells were differentially affected the three antihypertensive agents. After subtotal nephrectomy an increase in podocyte volume and mesangial cell number per glomerulus was noted. Nifedipine, and to a lesser extent ramipril, prevented mesangial cell hyperplasia. In contrast, only the ACE inhibitor ramipril, but not nifedipine or moxonidine prevented podocyte abnormalities, particularly podocyte hypertrophy.


CONCLUSIONS
(i) Despite comparable reduction in systolic blood pressure, different classes of antihypertensive agents had diverse effects on renal damage in subtotally nephrectomized rat. This observation is consistent with specific, non-hemodynamic actions of anti-hypertensives. (ii) Glomerular and tubulointerstitial damage are prevented by treatment with ACE inhibitors and antisympathotonic agents, but not with the calcium antagonist nifedipine. In contrast, renal vascular changes were also prevented by nifedipine. (iii) Only ACE inhibitors effectively inhibited podocyte hypertrophy and mesangial cell hyperplasia. Whether the superior effect of ACE inhibitors on glomerulosclerosis is related to inhibition of glomerular growth and podocyte hypertrophy as well as preservation of podocyte structure, or whether these findings are merely a passive reflection of greater efficacy, remains unresolved.
Amann
K
K
Departments of Pathology Heidelberg and Darmstadt, Department of Internal Medicine Ruperto Carola University, Heidelberg, Germany.
Nichols
C
C
Tornig
J
J
Schwarz
U
U
Zeier
M
M
Mall
G
G
Ritz
E
E
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002196:Capillaries / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology*; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000473:pathology*; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D009392:Nephrectomy; D009543:Nifedipine / Q000494:pharmacology*; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation
D000959:Antihypertensive Agents; D007093:Imidazoles; C043482:moxonidine; D009543:Nifedipine; D017257:Ramipril