Production of endothelin-1 by rat mesangial cells: regulation by tumor necrosis factor.

Endothelin-1 (ET-1) is produced by mesangial cells and potently regulates glomerular hemodynamics. The agents controlling mesangial cell ET-1 release are not well known; however, recent studies indicate that factors released during the inflammatory process can augment mesangial cell ET-1 production. One immune cell cytokine, tumor necrosis factor (TNF), is an important mediator of glomerular inflammation. Many of the renal effects of TNF are similar to those caused by ET-1, but the effect of TNF on mesangial cell ET-1 production is unknown. The current study examined the effect of TNF on ET-1 synthesis and release by mesangial cells. TNF, but not IL1, caused a dose-dependent and time-dependent increase in immunoreactive ET-1 in the supernatants of rat mesangial cells in culture. TNF augmentation of mesangial cell ET-1 release required at least 2 hours of exposure to a minimal concentration of 10 U/ml TNF. Blot hybridization analysis of mesangial cell RNA using a rat prepro-ET-1 cDNA revealed a 2.3 kb messenger RNA that was increased on exposure to TNF. The stimulatory effect of TNF on ET-1 release is not a general property of ET-1-producing cells because proximal tubule, medullary thick ascending limb, cortical collecting tubule, and inner medullary collecting duct cells did not increase ET-1 production on exposure to TNF. These data indicate that TNF is a potent stimulator of mesangial cell ET-1 production and raise the possibility that ET-1 could mediate, at least in part, renal dysfunction associated with high glomerular TNF levels.