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.