FOSINOPRIL AMELIORATES EXOGENOUS CHOLESTEROL-INDUCED INCIPIENT GLOMERULAR-LESIONS IN OBESE ZUCKER RATS - EFFECTS ON EICOSANOID SECRETION

Background. To date, the role of dietary cholesterol as a risk factor for some diabetic nephrophathy, such as mesangial expansion and glomer ular lesions, is unknown. Controversy also exists regarding the effect s of prostaglandin-induced changes in glomerular haemodynamics on the appearance of glomerulosclerosis. Methods. We have used obese Zucker r ats (OZRs) as a model of early nephrophathy to evaluate the effect of hypercholesterolaemic diet on glomerular prostaglandin secretion and o n the development of glomerular lesions. Due to the role of angiotensi n II (Ang II) in glomerular haemodynamics, we have also evaluated its effects on glomerular eicosanoid secretion. Furthermore, as it has bee n suggested recently by clinical studies that angiotensin-converting e nzyme inhibitors (ACEIs) reduce serum lipids associated with proteinur ia, we have also evaluated the effect of the ACEI, fosinopril, both in vivo and in vitro, using 24 h glomeruli cultures. Results. Results sh owed that a cholesterol-rich diet significantly increased serum choles terol, proteinuria and glomerular eicosanoid secretion, and caused mac rophage-ED1 cell deposits in the glomerular mesangium. Segmentary lesi ons only appeared in those rats with the highest percentage of glomeru lar xanthomatous (macrophage-ED1) cells. Ang II, per se, caused a mark ed rise in glomerular prosaglandin E-2 and thromboxane B-2. The inhibi tion of Ang II synthesis with fosinopril reduced all the parameters li sted above, whereas Ang II (10(-6) M) increased the secretion of TxB(2 ) and tended to increase PGE(2) secretion in glomerular culture. Concl usions. In conclusion, exogenous cholesterol per se may contribute to nephropathy by increasing eicosanoid secretion, serum lipid profile, u rinary protein excretion and the development of glomerular lesions. Fo sinopril reduced all these parameters probably by its effects on Ang I I.