P2X7 Deficiency Attenuates Renal Injury in Experimental Glomerulonephritis

Abstract

The P2X 7 receptor is a ligand-gated cation channel that is normally expressed by a variety of immune cells, including macrophages and lymphocytes. Because it leads to membrane blebbing, release of IL-1␤, and cell death by apoptosis or necrosis, it is a potential therapeutic target for a variety of inflammatory diseases. Although the P2X 7 receptor is usually not detectable in normal renal tissue, we previously reported increased expression of both mRNA and protein in mesangial cells and macrophages infiltrating the glomeruli in animal models of antibody-mediated glomerulonephritis. In this study, we used P2X 7 -knockout mice in the same experimental model of glomerulonephritis and found that P2X 7 deficiency was significantly renoprotective compared with wild-type controls, evidenced by better renal function, a striking reduction in proteinuria, and decreased histologic glomerular injury. In addition, the selective P2X 7 antagonist A-438079 prevented the development of antibody-mediated glomerulonephritis in rats. These results support a proinflammatory role for P2X 7 in immune-mediated renal injury and suggest that the P2X 7 receptor is a potential therapeutic target.

Loss of P2X7 nucleotide receptor function leads to abnormal fat distribution in mice

“…The function of P2X7 in collecting duct remains poorly understood. A previous study reported no abnormalities in renal morphology or histology in a different P2X7 KO mouse model (6-to 8-week-old female mice) [51]. In the present Fig.…”

“…This mouse model has been studied extensively; however, most studies have focused on the phenotype of younger animals. It has previously been reported that the Pfizer KO mouse displays no gross phenotypic differences at early ages [19,33,51]. In the present study, we allowed these mice to age, which revealed an unexpected increase in body mass due to greater lipid accumulation in older male KO mice.…”

P2X7 receptor antagonism attenuates the hypertension and renal injury in Dahl salt-sensitive rats

“…P2X 7 mRNA expression levels were determined by real-time RT-PCR, by using a commercial kit (Rn00570451_m1; Applied Biosystems, Foster City, CA, USA), and normalized for the expression of GAPDH mRNA (4352338E; Applied Biosystems). These measurements were expressed as log 10 [2 35-CT1 /2 25-CT2 ], where 2 35-CT1 and 2 correspond to the expression levels of P2X 7 and GAPDH mRNA, respectively.…”

“…2,3,25 Indeed, P2X 7 has recently been reported to be involved in various inflammatory processes of different pathological conditions, such as cerebral infarction 26 or ischemia, 27,28 lung inflammation and emphysema, 29 allergic airway inflammation, 30 unilateral urethral obstructive nephropathy 9 and accelerated nephrotoxic nephritis. 10 Several recent studies have provided convincing evidence that the renal proinflammmatory response has an important role in mediating salt-sensitive hypertension. 31,32 In a previous study, quantitative trait locus analysis identified the P2X 7 gene as a candidate gene for hypertension, by using F2 rats derived from DS and LEW rats.…”

“…2,3 P2X 7 has been reported to be involved in various nephropathy models, such as glomerular injury caused by diabetes and hypertension, 8 unilateral ureteral obstruction 9 and glomerulonephritis. 10 Dahl salt-sensitive (DS) rats fed on a high-sodium diet characteristically develop attenuated pressure natriuresis, hypertension and progressive renal injury, and this model has been widely used to study salt-sensitive hypertension. 11,12 In a previous study, we performed a genome-wide quantitative trait locus mapping analysis for blood pressure by using F2 rats derived from DS and Lewis (LEW) rats, and we identified a region on chromosome 12 near the D12Arb6 marker that influenced blood pressure.…”