Extracellular nucleotides as signalling molecules for renal mesangial cells

1. Glomerular diseases frequently cause chronic renal failure which ultimately requires dialysis and kidney transplantation. The events leading to destruction of the glomerular filtration apparatus include injury of glomerular cells, aggregation of thrombocytes and infiltration of immune cells into the glomerulus. 2. Nucleotides (e.g. ATP and UTP) are present in all glomerular cell types as well as in thrombocytes. The release of nucleotides into the extracellular space occurs after damage of glomerular cells and aggregation of thrombocytes. Several in vitro and in vivo findings indicate that extracellular nucleotides may play a role as pro-inflammatory mediators in glomerulonephritis. 3. A hallmark finding in kidney biopsies from patients with glomerulonephritis is proliferation of glomerular mesangial cells. Cell culture studies demonstrated that extracellular ATP (10-300 microM) stimulated growth of mesangial cells. The mitogenic effect of ATP was potentiated in the presence of multiple growth factors. 4. Nucleotide-induced signalling in mesangial cells included an increase of intracellular calcium, activation of phosphatidylinositol-specific phospholipase C and phospholipase D, inhibition of adenylylcyclase, stimulation of mitogen-activated protein kinase and increased expression of the immediate early genes, c-fos, c-jun and Egr-1. 5. In previous studies of experimental mesangioproliferative glomerulonephritis, exogenously given ADP beta S and ATP gamma S have been shown to aggravate the course of the disease, while 2-chloroadenosine had beneficial effects. 6. Taken together, these findings support the concept that nucleotides may function as proinflammatory mediators in glomerulonephritis while adenosine may have antiinflammatory effects.