Vasoactive agents modulate matrix metalloproteinase-2 activity by mesangial cells.
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.
Singhal
P C
PC
Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, New York 11040, USA.
Sagar
S
S
Garg
P
P
Bansal
V
V
D017311:Amlodipine / Q000494:pharmacology; D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018093:Gelatinases / Q000378:metabolism*; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D007213:Indomethacin / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2; D008469:Meclofenamic Acid / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000378:metabolism*; D051381:Rats; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D002121:Calcium Channel Blockers; D002317:Cardiovascular Agents; D016861:Cyclooxygenase Inhibitors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000804:Angiotensin II; D017311:Amlodipine; D008469:Meclofenamic Acid; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D015232:Dinoprostone; D007213:Indomethacin