Endothelium-derived vasoactive mediators and renal glomerular function.

Abstract

Glomerular endothelial cells are located in extremely close proximity to glomerular mesangial cells, without intervening basement membrane. This close apposition of the two cell types suggest that interactions between the cells should readily occur. Given that endothelial cells are known to produce mediators which regulate the tone of underlying vascular smooth muscle cells, the hypothesis that glomerular endothelial cells can produce endothelium-derived relaxation factor and the potent vasoconstrictor endothelin-1 was examined. Pure cultures of glomerular endothelial cells were established in vitro. The cells expressed a number of characteristics that identified them as endothelial cells, namely Factor VIII related antigen, angiotensin I converting enzyme, and uptake of acetylated LDL. The glomerular endothelial cells responded to the calcium-mobilizing agonists bradykinin, ATP, thrombin and platelet activating factor with a significant rise in cytosolic calcium concentrations. Under basal conditions, the glomerular endothelial cells produced a mediator pharmacologically indistinguishable from EDRF, which raised cGMP levels in co-incubated mesangial cells approximately 4 to 5-fold. The calcium-mobilizing agonists further stimulated EDRF release by glomerular endothelial cells. Glomerular endothelial cells in culture were also found to express mRNA for endothelin-1, and to secrete this peptide into their supernatant. Furthermore, the calcium-mobilizing agonists markedly stimulated endothelin-1 release by activating endothelin-1 gene transcription. Glomerular mesangial cells respond to EDRF with a rise in cytosolic cGMP concentration and relaxation, and to endothelin-1 with a rise in cytosolic calcium concentration and contraction. It is therefore proposed that local release of EDRF and endothelin-1 by glomerular endothelial cells may participate in the regulation of glomerular hemodynamics through alterations in mesangial cell contractile tone.