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Vasoactive agents modulate matrix metalloproteinase-2 activity by mesangial cells
1Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, New York 11040, USA.
Abstract:
Vasoactive agents alter proteinuria by modulating glomerular hemodynamics. The authors hypothesized that vasoactive agents may be altering degradation of the collagen component of glomerular basement membrane, which also may be contributing to proteinuria. Mesangial cells treated with 10(-6) M angiotensin II had higher (P < 0.01) metalloproteinase activity (MA) when compared with control cells. This effect of angiotensin II was dose dependent. Amlodipine (10(-6) M), a calcium channel blocker, inhibited MA (control, 5.86 +/- 0.08 microgram versus 4.13 +/- 0.06 microgram gelatin degraded/mg protein, P < 0.001). The decrease in mesangial MA caused by amlodipine also occurred in a dose dependent manner. Amlodipine attenuated (P < 0.05) angiotensin II-stimulated MA (control, 6.69 +/- 0.30 micrograms, angiotensin II, 10.68 +/- 0.49 micrograms, angiotensin II+amlodipine 8.29 +/- 0.30 micrograms gelatin degraded/mg protein). Prostaglandin E2 increased (P < 0.001) MA (control, 10.22 +/- 0.9 micrograms versus prostaglandin E2, 17.9 +/- 0.9 micrograms gelatin degraded/mg protein), whereas indomethacin, a prostaglandin inhibitor, attenuated the metalloproteinase activity (control, 9.67 +/- 0.32 micrograms vs. 10(-6) M indomethacin, 4.22 +/- 0.31 micrograms gelatin degraded/mg protein, P < 0.001). Indomethacin also inhibited angiotensin II-stimulated MA (angiotensin II, 18.66 +/- 0.46 vs. angiotensin II+indomethacin, 11.86 +/- 0.56 micrograms degraded/mg protein, P < 0.001). Similarly, meclofenamate, another prostaglandin inhibitor, attenuated (P < 0.001) angiotensin II-induced MA. Because angiotensin II increases prostaglandin E2 synthesis by mesangial cells, it appears that increased MA, induced by angiotensin II, may be mediated partly through the generation of prostaglandin E2.
Insights
Vasoactive agents like angiotensin II increase metalloproteinase activity (MA) in mesangial cells, potentially contributing to proteinuria. This effect is partly mediated by prostaglandin E2 and can be inhibited by amlodipine and prostaglandin inhibitors.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Vasoactive agents influence proteinuria by altering glomerular hemodynamics.
- The collagen component of the glomerular basement membrane is a potential target for vasoactive agents, influencing proteinuria.
- Mesangial cells play a role in regulating glomerular function and extracellular matrix degradation.
Purpose of the Study:
- To investigate the hypothesis that vasoactive agents alter metalloproteinase activity (MA) in mesangial cells.
- To determine the role of prostaglandin E2 in angiotensin II-induced MA.
- To evaluate the effects of amlodipine and prostaglandin inhibitors on MA.
Main Methods:
- Mesangial cells were treated with varying concentrations of angiotensin II.
- Metalloproteinase activity (MA) was measured using gelatin degradation assays.
- Cells were co-treated with angiotensin II and agents such as amlodipine, indomethacin, and meclofenamate.
Main Results:
- Angiotensin II significantly increased MA in mesangial cells in a dose-dependent manner.
- Amlodipine, a calcium channel blocker, inhibited both basal and angiotensin II-stimulated MA.
- Prostaglandin E2 increased MA, while prostaglandin inhibitors (indomethacin, meclofenamate) attenuated MA, including angiotensin II-induced activity.
Conclusions:
- Angiotensin II elevates MA in mesangial cells, suggesting a mechanism contributing to proteinuria.
- The increase in MA induced by angiotensin II appears to be partly mediated by prostaglandin E2 synthesis.
- Amlodipine and prostaglandin synthesis inhibitors demonstrate potential in modulating MA and may offer therapeutic benefits in proteinuric conditions.