CHOLESTEROL FEEDING ACCENTUATES THE CYCLOSPORINE-INDUCED ELEVATION OFRENAL PLASMINOGEN-ACTIVATOR INHIBITOR TYPE-1

Long-term cyclosporine (CsA) therapy is accompanied by the occurrence of hypercholesterolemia and renal interstitial fibrosis. The present s tudy investigates the effect of dietary cholesterol on CsA-induced lip id disturbances in the rat and on CsA nephrotoxicity. Since plasminoge n activator inhibitor type 1 (PAI-1) is a major inhibitor of matrix de gradation and elevated plasma PAI-1 levels are reported to be associat ed with increased low-density lipoprotein (LDL) cholesterol, PAI-1 was examined in the kidneys of rats fed a sodium-deficient diet, with or without cholesterol. After nine weeks, both diet groups were subdivide d into a CsA-treated group and a vehicle-treated group. Although chole sterol feeding significantly aggravated CsA-induced renal function imp airment, CsA-induced histological lesions were comparable in both diet groups. Cholesterol feeding significantly decreased high-density lipo protein (HDL) cholesterol irrespective of the treatment, while CsA tre atment significantly elevated serum triglycerides irrespective of the diet. Cholesterol feeding alone did not increase the number of infiltr ating cells in the renal interstitium. In contrast, in both diet group s CsA treatment caused a significant influx of macrophages, while comb ined treatment with CsA and cholesterol additionally elevated the numb er of T-helper cells in the cortex. In all rats, PAI-1 immunostaining was found mainly in intracellular vesicles (lysosomes) in proximal tub ules, which stained most intensely in fibrotic areas of kidneys from C sA-treated rats. Cholesterol feeding enhanced the CsA-induced elevatio n of renal PAI-1 immunostaining to a significant level. These results show that, although serum creatinine, PAI-1 staining and T cell influx were significantly increased in the cholesterol-fed CsA-treated group compared to the other groups, renal CsA-induced histological lesions were not influenced by cholesterol feeding after short-term (3 weeks) CsA administration. To what extent the more pronounced proximal tubula r PAI-1 (inhibitor of matrix degradation) immunostaining in fibrotic a reas in the cortex of cholesterol-fed CsA-treated rats contributes to the progression of CsA-induced renal fibrosis remains to be determined .