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Nephrology Dialysis Transplantation, Vol 13, Issue 9 2227-2233, Copyright © 1998 by Oxford University Press

ORIGINAL ARTICLES

Fosinopril ameliorates exogenous cholesterol-induced incipient glomerular lesions in obese Zucker rats. Effects on eicosanoid secretion

S Higueruelo, M Vaquero, C Pastor, R Galimany and R Romero
Nephrology Department, Hospital Universitari Germans Trias i Pujol, E-08916 Badalona, Spain; Corresponding author

Background: To date, the role of dietary cholesterol as a risk factor for some diabetic nephropathy, such as mesangial expansion and glomerular lesions, is unknown. Controversy also exists regarding the effects of prostaglandin-induced changes in glomerular haemodynamics on the appearance of glomerulo-sclerosis. Methods: We have used obese Zucker rats (OZRs) as a model of early nephropathy to evaluate the effect of hypercholesterolaemic diet on glomerular prostaglandin secretion and on the development of glomerular lesions. Due to the role of angiotensin II (Ang II) in glomerular haemaodynamics, we have also evaluated its effects on glomerular eicosanoid secretion. Furthermore, as it has been suggested recently by clinical studies that angiotensin-converting enzyme inhibitors (ACEIs) reduce serum lipids associated with proteinuria, we have also evaluated the effect of the ACEI, fosinopril, both in vivo and in vitro, using 24 h glomeruli cultures. Results: Results showed that a cholesterol-rich diet significantly increased serum cholesterol, proteinuria and glomerular eicosanoid secretion, and caused macrophage-ED1 cell deposits in the glomerular mesangium. Segmentary lesions only appeared in those rats with the highest percentage of glomerular xanthomatous (macrophage-ED1) cells. Ang II, per se, caused a marked rise in glomerular prostaglandin E2 and thromboxane B2. The inhibition of Ang II synthesis with fosinopril reduced all the parameters listed above whereas Ang II (10-6 M) increased the secretion of TxB2 and tended to increase PGE2 secretion in glomerular culture. Conclusions: In conclusion, exogenous cholesterol per se may contribute to nephropathy by increasing eicosanoid secretion, serum lipid profile, urinary protein excretion and the development of glomerular lesions. Fosinopril reduced all these parameters probably by its effects on Ang II. Key words: angiotensin-converting enzyme inhibitors; angiotensin II; eicosanoid secretion; incipient glomerular lesion; macrophage-ED1 cells; nephropathy; xanthomatous cells
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