Modulation of anti-Thy1 nephritis in the rat by adenine nucleotides. Evidence for an anti-inflammatory role for nucleotidases

Abstract

Extracellular adenine nucleotides are considered mediators of inflammation because they modulate functions of neutrophils and platelets. Until now, this role for adenine nucleotides has not been studied in vivo. In particular in the rat kidney, where ATP- and ADPase activity is present in the glomerular basement membrane, studies about the role of nucleotides may increase our understanding of the dynamics of glomerulonephritis (GN). Therefore, we examined effects of adenine derivatives ATP gamma S, ADP beta S and 2chloro-adenosine (2chloro-ADO) in vitro and during anti-Thy1 GN. The in vitro results show that ADP beta S and ATP gamma S are not degraded by glomerular nucleotidases but, on the other hand do stimulate O2- production of peritoneal exudate cells (PEC). In contrast, 2chloro-ADO significantly inhibits O2- production of peritoneal exudate cells. For in vivo studies rats were rendered nephritic by intravenous injection of monoclonal anti-Thy1 IgG (5 mg/kg body weight). Subsequently, rats were treated with saline (group 1, N = 10), 2chloro-ADO (group 2, N = 10), ADP beta S (group 3, N = 10) or ATP gamma S (group 4, N = 10). All analogs (10 mg/kg body weight) were administered both at t = 0 and t = 12 hour. After 24 hours, rats were sacrificed and kidneys were examined histochemically. In an additional group of nephritic rats (N = 5) proteinuria was studied after 2-chloro-ADO treatment. Results show increased intraglomerular platelet aggregation in nephritic rats treated with ADP beta S, whereas 2chloro-ADO inhibits aggregation significantly as compared with nephritic rats receiving saline. The percentage of granulocytes producing O2- is significantly increased in glomeruli after treatment of nephritic rats with ATP gamma S, whereas cell influx itself is not changed. In contrast, 2chloro-ADO inhibits intraglomerular O2- production, which is associated with the complete inhibition of proteinuria in the early phase of anti-Thy1 GN. These data demonstrate significant pro-inflammatory activities of extracellular adenine nucleotides during anti-Thy1 GN suggesting an anti-inflammatory role for glomerular ATP/ADPase, which in concert with 5' nucleotidase converts ATP and ADP to antiinflammatory ADO.