Hypercholesterolemia, a major risk factor for atherosclerosis, is present in many patients with chronic renal failure (CRF). The present study was carried out in order to determine the mechanisms which underlie this increase in serum cholesterol levels and to test the feasibility of using lovastatin, a HMG-CoA reductase inhibitor in its treatment. / A mouse model of surgically-induced CRF was employed in the experiments. Five weeks after the onset of renal failure, the mice were characterized with regard to various biochemical and hematological parameters. At this time, treatment with lovastatin was initiated. The drug (50, 100 and 200 mg/kg BW/day) was incorporated in powdered diet and was given fresh daily for four weeks. Upon sacrifice, blood was collected for the estimation of blood urea nitrogen and serum lipids and livers were excised for the measurement of hepatic HMG-CoA reductase activity. / The mice exhibited the major manifestations of CRF--retention of nitrogenous wastes, elevated levels of alkaline phosphatase, suggesting the presence of bone disease, and severe anemia. CRF mice also had elevated serum total cholesterol levels with a concomitant, but not significantly correlated, increase in hepatic HMG-CoA reductase activity. Furthermore, their serum lipoprotein profiles were abnormal. Treatment with lovastatin resulted in a dose-dependent reduction in serum total cholesterol levels and correction of the serum lipoprotein profile. However, hepatic HMG-CoA reductase activity was unchanged. / These results indicate that the hypercholesterolemia observed in CRF mice is probably due to an increase in de novo synthesis of cholesterol in both the liver and extranepatic tissues. Lovastatin may decrease serum total cholesterol levels in CRF mice by inhibiting peripheral, rather than hepatic, HMG-CoA reductase activity.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.68259 |
| Date | January 1992 |
| Creators | Subang, Maria Cristina |
| Contributors | Stewart-Phillips, Jean L. (advisor), Gagnon, Raymonde F. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Department of Physiology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001482636, proquestno: AAIMM94529, Theses scanned by UMI/ProQuest. |
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