Tumor necrosis factor-induced contraction of cultured rat mesangial cells : interaction with angiotensin II

The role of tumor necrosis factor α in the regulation of renal function, particularly glomerular filtration rate, has not been completely defined. This study was designed to assess the intrinsic role of this cytokine on glomerular filtration rate by analyzing its short-term effect on the degree of contraction in cultured rat mesangial cells, not only directly but also in the presence of angiotensin II. Contraction was evaluated both morphologically- by measuring planar cell surface area of cultured rat mesangial cells and glomerular cross-sectional area of isolated rat glomeruli-and biochemically- by analyzing myosin light-chain phosphorylation in cells. Tumor necrosis factor α significantly decreased planar cell surface area in a dose-dependent and time-dependent manner, an effect completely abolished by preincubation of the cells with platelet-activating factor receptor antagonists BN 52021 and alprazolam. This effect was also observed in the presence of angiotensin II, whether tumor necrosis factor α was added before or after angiotensin II, increasing the reduction in planar cell surface area induced by angiotensin II in both cases. Changes in planar cell surface area were evident not only when the absolute values of this parameter were considered but also when the percentage of contracted cells (cells with a planar cell surface area reduction >10%) was analyzed. Tumor necrosis factor α also induced a significant reduction of glomerular cross-sectional area in isolated rat glomeruli. The results of the morphologic studies were supported by myosin light-chain phosphorylation experiments. This parameter increased significantly in the presence of tumor necrosis factor α as a function of the incubation time (short-term studies, between 30 and 120 minutes), whereas the combined effect of tumor necrosis factor α and angiotensin II on myosin light-chain phosphorylation was significantly more important than the isolated action of either tumor necrosis factor α or angiotensin II. These results suggest that on a short-term basis tumor necrosis factor α can reduce the area of mesangial cells and glomeruli and can even potentiate the contractile action of angiotensin II, modifying the ultrafiltration coefficient. This explains the decrease in glomerular filtration rate in some pathologic situations characterized by an increase in tumor necrosis factor α release. Platelet-activating facfor could be involved in the genesis of these effects