SIMULATED GLOMERULAR PRESSURE MODULATES MESANGIAL CELL 72-KDA METALLOPROTEINASE ACTIVITY

Glomerular hypertension has been considered to play an important role in the development of glomerulosclerosis. Mesangial expansion, a precu rsor of glomerulosclerosis, may be dependent not only on synthesis of matrix but also on degradation of the deposited matrix. In the present study we investigated the effect of simulated glomerular pressure on 72 kDa metalloproteinase activity (measured as degradation of gelatin) of mesangial cells. To simulate glomerular pressure conditions we hav e used an in vitro mechanical stretch/relaxation system as well as an alternative system which allowed direct application of pressure on mes angial cells. Mesangial cells were grown either under control (no adde d pressure), stretch/relaxation, or direct mean pressure of 45-50 mm H g (physiologic glomerular pressure) conditions. Mesangial cells grown under stretch/relaxation showed a higher (P < 0.02) level of 72 kDa me talloproteinase activity when compared with control cells (control, 6. 9 +/- 0.8 vs. stretch, 9.9 +/- 0.5 ng gelatin degraded/mu g protein). Similarly, direct simulated glomerular pressure increased (P < 0.01) m esangial cell 72 kDa metalloproteinase activity when compared with con trol cells. The effect of mechanical strain on mesangial cell 72 kDa m etalloproteinase activity peaked at the end of the third day (control, 4.5 +/- 1.1 vs. stretch 15.3 +/- 1.1 ng gelatin degraded/mu g protein , P < 0.001). Both mechanical strain and direct pressure to mesangial cells modulated 72 kDa metalloproteinase activity in a dose dependent manner. Mechanical stretch equivalent to normal simulated glomerular p ressure increased mesangial 72 kDa metalloproteinase activity by 88%; whereas mesangial cell 72 kDa metalloproteinase activity declined to b asal levels at higher simulated glomerular pressure (equivalent to 100 mm Hg). Likewise, direct higher pressure (100 mm Hg) also lowered 72 kDa metalloproteinase activity to basal levels. These results indicate that higher glomerular pressure inhibits degradation of type IV colla gen. This may cause an accumulation of extracellular matrix and may th us be contributing to the expansion of the mesangium.