title: Cholesterol feeding accentuates the cyclosporine-induced elevation of renal plasminogen activator inhibitor type 1.
abstract: Long-term cyclosporine (CsA) therapy is accompanied by the occurrence of hypercholesterolemia and renal interstitial fibrosis. The present study investigates the effect of dietary cholesterol on CsA-induced lipid disturbances in the rat and on CsA nephrotoxicity. Since plasminogen activator inhibitor type 1 (PAI-1) is a major inhibitor of matrix degradation and elevated plasma PAI-1 levels are reported to be associated 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 subdivided into a CsA-treated group and a vehicle-treated group. Although cholesterol feeding significantly aggravated CsA-induced renal function impairment, CsA-induced histological lesions were comparable in both diet groups. Cholesterol feeding significantly decreased high-density lipoprotein (HDL) cholesterol irrespective of the treatment, while CsA treatment significantly elevated serum triglycerides irrespective of the diet. Cholesterol feeding alone did not increase the number of infiltrating cells in the renal interstitium. In contrast, in both diet groups CsA treatment caused a significant influx of macrophages, while combined treatment with CsA and cholesterol additionally elevated the number of T-helper cells in the cortex. In all rats, PAI-1 immunostaining was found mainly in intracellular vesicles (lysosomes) in proximal tubules, which stained most intensely in fibrotic areas of kidneys from CsA-treated rats. Cholesterol feeding enhanced the CsA-induced elevation 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 tubular PAI-1 (inhibitor of matrix degradation) immunostaining in fibrotic areas in the cortex of cholesterol-fed CsA-treated rats contributes to the progression of CsA-induced renal fibrosis remains to be determined.
authors.affiliation: Department of Nephrology-Hypertension, University of Antwerp, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Duymelinck
authors.forename: S E
authors.initials: SE
authors.lastname: Dauwe
authors.forename: E J
authors.initials: EJ
authors.lastname: Nouwen
authors.forename: M E
authors.initials: ME
authors.lastname: De Broe
authors.forename: G A
authors.initials: GA
authors.lastname: Verpooten
mesh_terms: D000818:Animals; D001835:Body Weight; D002455:Cell Division; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D007150:Immunohistochemistry / Q000379:methods; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008055:Lipids / Q000097:blood; D008297:Male; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013194:Staining and Labeling
chemical_list: D002791:Cholesterol, Dietary; D007166:Immunosuppressive Agents; D008055:Lipids; D017395:Plasminogen Activator Inhibitor 1; D016572:Cyclosporine