Native and oxidized low density lipoproteins modulate mesangial cell apoptosis
1Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, New York, USA.
Abstract:
Hyperlipidemia has been demonstrated to contribute to hypercellularity of the mesangium in experimental animal models of glomerulosclerosis. We studied whether it also has the potential to convert a hypercellular mesangium into a hypocellular one by inducing mesangial cell (MC) apoptosis. Low density lipoprotein (LDL) enhanced (P < 0.001) mouse mesangial cell (MMC) proliferation at lower concentrations (control, 10.3 +/- 0.3 vs. LDL 100 micrograms/ml, 24.2 +/- 0.3 x 10(4) cells/ml) but augmented (P < 0.001) apoptosis at higher concentrations (control, 5.6 +/- 0.5% vs. LDL, 500 micrograms/ml 26.2 +/- 3.4% apoptotic cells/field). Oxidized (OX) LDL enhanced MMC apoptosis in concentrations of 50 to 200 micrograms/dl. There was a direct relationship between MMC apoptosis and oxidation of LDL as judged by measuring thiobarbituric acid reactive species (TBARS). Since superoxide dismutase (SOD) attenuated (P < 0.001) LDL-induced MMC apoptosis, it seems to be mediated through the generation of free radicals by mesangial cells (control, 4.3 +/- 1.5%; LDL, 200 micrograms/ml, 19.4 +/- 0.5%; LDL + SOD, 8.1 +/- 1.3% apoptotic cells/field). LDL also induced a similar effect on human mesangial cells. These studies were further confirmed by DNA fragment assays and ELISA for programmed cell death. LDL treated cells also showed enhanced mRNA expression for RSG-2, a marker for active cell death. These in vitro results provide a basis for the speculation that LDL has the potential to cause an initial hypercellular and subsequent hypocellular mesangium in the course of the development of glomerulosclerosis.
Insights
High levels of low-density lipoprotein (LDL) can initially increase mesangial cell proliferation but then induce apoptosis, leading to a hypocellular mesangium in glomerulosclerosis.
Area of Science:
- Nephrology
- Cell Biology
- Cardiovascular Research
Background:
- Hyperlipidemia is linked to mesangial hypercellularity in glomerulosclerosis.
- The role of lipids in mesangial cell apoptosis remains unclear.
Purpose of the Study:
- To investigate if low-density lipoprotein (LDL) can induce mesangial cell apoptosis.
- To explore the mechanisms behind LDL-induced mesangial cell apoptosis.
Main Methods:
- In vitro studies using mouse and human mesangial cells.
- Assessing cell proliferation and apoptosis via cell counts, DNA fragmentation assays, ELISA, and RSG-2 mRNA expression.
- Measuring thiobarbituric acid reactive species (TBARS) to assess LDL oxidation.
- Evaluating the effect of superoxide dismutase (SOD) on apoptosis.
Main Results:
- LDL increased mesangial cell proliferation at lower concentrations and induced apoptosis at higher concentrations.
- Oxidized LDL (OX-LDL) significantly enhanced mesangial cell apoptosis.
- LDL-induced apoptosis was mediated by free radical generation, as evidenced by TBARS and attenuation by SOD.
- Similar effects were observed in human mesangial cells.
Conclusions:
- LDL has a dual effect on mesangial cells, promoting proliferation and then apoptosis.
- Oxidation of LDL and free radical generation are key mechanisms in LDL-induced mesangial cell death.
- These findings suggest LDL contributes to the transition from hypercellular to hypocellular mesangium in glomerulosclerosis.
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