Prostaglandin E2 stimulates expression of matrix metalloproteinase 2 in cultured rat mesangial cells

Abstract

Prostaglandins of the E-series have been demonstrated to reduce extracellular accumulation of collagens in some models of glomerulonephritis. This effect is partially due to reduction of collagen formation by mesangial cells. The potential effects of prostaglandins on the expression of collagen degrading enzymes in mesangial cells are largely unknown. Since rat mesangial cells generate a matrix metalloproteinase 2 (MMP-2) that specifically degrades collagen type IV, the effects of prostaglandin E2 (PGE2) on transcription, steady-state mRNA levels, extracellular enzyme activity and protein concentration of this proteinase were evaluated. Mesangial cells (MC) were incubated with PGE2 (2 microM) for different time-periods (1 to 48 hr), and steady-state mRNA levels of MMP-2 were determined by Northern blotting. PGE2 increased MMP-2 mRNA levels beginning at one hour of incubation and remained elevated up to 24 hours. Nuclear run off experiments revealed that the PGE2-induced increase in mRNA expression for MMP-2 is due to stimulated gene transcription. Western blot analysis and zymography revealed that MMP-2 protein production and enzyme activity was also enhanced by PGE2. The cAMP analogue 8-bromo-cAMP increased MMP-2 mRNA levels, suggesting that PGE2-induced generation of intracellular cAMP plays a role in MMP-2 induction in MC. These studies demonstrate that PGE2 stimulates the transcription, protein formation and enzyme activity of MMP-2 in cultured rat MC. This effect may contribute to the prostaglandin mediated reduction of extracellular collagen deposition in glomerulonephritis.