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Published on: November 17, 2016
The effect of cholesterol overload on mouse kidney and kidney-derived cells
Shoko Honzumi1, Miho Takeuchi1, Mizuki Kurihara1
1a Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences , Chiba University , Chiba , Japan.
Introduction:
Dyslipidemia is one of the onset and risk factors of chronic kidney disease and renal function drop is seen in lipoprotein abnormal animal models. However, the detailed molecular mechanism of renal lipotoxicity has not been clarified. Therefore, the present study aimed to investigate the influence of cholesterol overload using mouse kidney tissue and kidney-derived cultured cells.
Methods:
C57BL/6 mice were fed normal diet (ND) or 1.25% cholesterol-containing high-cholesterol diet (HCD) for 11 weeks, and we used megalin as a proximal tubule marker for immunohistology. We added beta-very low density lipoprotein (βVLDL) to kidney-derived cells and examined the effect of cholesterol overload on megalin protein and mRNA expression level, cell proliferation and cholesterol content in cells.
Results:
In the kidney of HCD mice, the gap between glomerulus and the surrounding Bowman's capsule decreased and the expression level of megalin decreased. After βVLDL treatment to the cells, the protein expression and mRNA expression level of megalin decreased and cell proliferation was restrained. We also observed an increase in cholesterol accumulation in the cell and free cholesterol/phospholipid ratios increased.
Conclusions:
These findings suggest that the increased cholesterol load on kidney contribute to the decrease of megalin and the overloaded cholesterol is taken into the renal tubule epithelial cells, causing suppression on cell proliferation, which may be the cause of kidney damage.
Insights
High cholesterol diets cause kidney damage by reducing megalin levels and inhibiting cell proliferation in renal tubule epithelial cells. This study investigated the molecular mechanisms of cholesterol overload in kidney tissues and cells.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Dyslipidemia is a significant risk factor for chronic kidney disease (CKD) and renal dysfunction.
- The precise molecular mechanisms underlying renal lipotoxicity remain incompletely understood.
- This study investigates the impact of cholesterol overload on kidney physiology and cellular function.
Purpose of the Study:
- To elucidate the effects of cholesterol overload on kidney tissue and cultured renal cells.
- To examine the molecular mechanisms of renal lipotoxicity in the context of dyslipidemia.
- To identify potential cellular targets affected by excess cholesterol in the kidneys.
Main Methods:
- High-cholesterol diet (HCD) administration to C57BL/6 mice for 11 weeks.
- Immunohistological analysis of kidney tissue, using megalin as a proximal tubule marker.
- In vitro studies involving beta-very low density lipoprotein (βVLDL) treatment of kidney-derived cells to assess megalin expression, cell proliferation, and cholesterol content.
Main Results:
- HCD-fed mice exhibited reduced glomerular-capsular space and decreased megalin expression in kidney tissue.
- βVLDL treatment led to decreased megalin protein and mRNA levels in cultured renal cells.
- Cholesterol overload suppressed cell proliferation and increased intracellular cholesterol accumulation and free cholesterol/phospholipid ratios.
Conclusions:
- Increased cholesterol load in the kidney contributes to megalin downregulation.
- Overloaded cholesterol uptake by renal tubule epithelial cells suppresses proliferation, potentially causing kidney damage.
- These findings highlight a molecular mechanism linking dyslipidemia to CKD progression.
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