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Pathogenesis of cholesterol-induced glomerulosclerosis in guinea pigs

The role of cholesterol-rich diet and of high protein supplement on the development of a glomerular lesion was studied in male guinea pigs. The possible pathogenesis of lipid-induced glomerulosclerosis was investigated. Four experiments were carried out. Four groups of guinea pigs were used in experiment I: CONT group was kept on normal guinea pig chow for 70 days; HC group was kept on 2% cholesterol diet for 70 days; HP group was kept on 50% casein diet for 70 days, and HCHP group received 2% cholesterol diet for 30 days and 2% cholesterol/50% casein diet for another 40 days. In experiment II two groups were used: CONT group and acetyl phenylhydrazine (APH)-treated group in which haemolytic anaemia was induced. In the third experiment the same dietary regimens as described in experiment I were used. In experiment IV three groups, namely CONT, HC, and HCHP, were employed. The animals in experiment IV were sacrificed after 5, 10, and 30 days. The first experiment explored the role of high cholesterol - and high cholesterol/high protein diet in the development of glomerulosclerosis. The other three experiments were designed to learn about the possible mechanism of lipid-induced glomerulosclerosis. Lipid analyses of plasma, erythrocytes and kidney tissue as well as complete blood count, erythrocyte osmotic fragility and blood cell morphology studies were performed. Kidney histology, histochemistry, immunohistochemistry, electron microscopy, morphometry, and renal and liver function tests were also carried out. De novo cholesterol synthesis was assessed by measuring HMG COA reductase activity and incorporation of tritiated water into cholesterol in the kidneys. Cholesterol-fed animals showed decreased weight gain, increased cholesterol concentration in plasma, erythrocytes, and kidney tissue. Haemolytic anaemia was documented after 70 days on this dietary regimen. Glomerular proliferation lesion was first noted at day 30 and progressed by day 70. Moderate proteinuria and haematuria were observed at day 70. Addition of protein to the high cholesterol diet led to a further decrease in weight gain. It also increased the mortality rate to 40% by day 70. The glomerular lesion, proteinuria and haematuria, and possibly haemolysis were more marked in the HCHP group. No causal relationship was found between liver function, immune complexes, haemolysis and glomerulosclerosis. Serum phosphate levels did not differ among the groups. The lipid found in the kidney of both HC and HCHP groups was mostly of plasma origin, since the kidney cholesterol de novo synthesis was suppressed in these two groups compared to the CONT group. There was a concommitant increase in the lipid content of kidney tissue and the mesangial expansion (MA/GTA) at day 30. No significant increase in the intraglomerular monocyte/macrophage was found at day 30 in the HCHP group compared to the HC group. However, a significant correlation (r=0.678, p 0.001) was found between the number of these cells and MA/GTA ratio among the four experimental groups at day 70.
These data indicate that lipid deposits in kidney tissue may induce a glomerulosclerotic lesion in the absence of monocytes. However, these cells likely augment the proliferation of mesangial cells. We postulate that high protein diet could worsen the lipid-induced glomerular lesion by increasing delivery of abnormal lipoproteins to the kidney which could trigger mesangial cellular proliferation directly and indirectly by a macrophage-mediated process. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

Identiferoai:union.ndltd.org:UBC/oai:circle.library.ubc.ca:2429/26949
Date January 1987
CreatorsAl-Shebeb, Taha H.
PublisherUniversity of British Columbia
Source SetsUniversity of British Columbia
LanguageEnglish
Detected LanguageEnglish
TypeText, Thesis/Dissertation
RightsFor non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.

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