Increased expression of the pro-apoptotic ATP-sensitive P2X7 receptor in experimental and human glomerulonephritis

Abstract

The involvement of IL-1beta and other pro-inflammatory cytokines in most forms of glomerulonephritis is now well established. The P2X(7) receptor, an ATP-sensitive P2X receptor, functions not only as a non-selective cation channel, but it is also involved in the rapid processing and release of IL-1beta, apoptosis and necrotic cell death. Therefore, we wanted to investigate if expression of this receptor is altered in the glomeruli of rodent models of glomerulonephritis. P2X(7) receptor protein expression was investigated using immunohistochemistry, and apoptosis was assessed using the TUNEL assay and caspase-3 immunostaining. Real-time PCR with gene-specific primers was used to detect P2X(7), IL-1beta, p53, bax and bcl-2 mRNA expression. Although the levels of the P2X(7) receptor protein in mouse kidney are normally very low, or undetectable, we detected an increase in glomerular expression of this receptor and an increase in glomerular apoptotic cells in a mouse model of accelerated nephrotoxic nephritis. We also observed increased glomerular and tubular expression of the P2X(7) receptor protein in renal biopsy tissue of patients with autoimmune-related glomerulonephritis. Furthermore, P2X(7) receptor mRNA increased in the kidneys of a rat model of proliferative glomerulonephritis and this coincided with the onset of proteinuria. We also observed increased mRNA expression of Il-1beta and the pro-apoptotic markers p53 and bax, but not of anti-apoptotic bcl-2. Although there is an association between expression of the pro-inflammatory and pro-apoptotic P2X(7) receptor and glomerulonephritis in these rodent models, and in at least one form of human glomerulonephritis, the underlying relationship and its functional significance remain to be explored.