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      The P2X 7 ATP Receptor in the Kidney: A Matter of Life or Death?

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          P2X<sub>7</sub> is an intriguing membrane receptor for the extracellular nucleotide ATP, which functions as a ligand-gated ion channel; it can activate cell membrane permeabilization and also has a wide range of downstream signaling pathways, including mediation of inflammatory responses and modulation of cell turnover. Despite recent identification of P2X<sub>7</sub> receptor protein in the renal tract, the biological and potential pathological functions of this receptor and its signaling cascades in the kidney are not yet fully understood. P2X<sub>7</sub> receptor protein is expressed in normal kidney development, predominantly in the condensing mesenchyme, and later in the maturing and adult derivatives of the ureteric bud. Glomerular expression of the molecule is scarce in normal kidney, but is upregulated in chronic and inflammatory conditions, suggesting a role in the inflammatory response or in repair and remodeling in these settings. P2X<sub>7</sub> receptor expression in the adult collecting ducts of murine kidney, as well as the collecting duct cysts in autosomal recessive polycystic kidney disease, has been described and agonists of the receptor can modulate the development of renal cysts in an in vitro model of cyst formation derived from the cpk/cpk mouse. Further investigation of the function of the P2X<sub>7</sub> receptor in normal and abnormal kidneys might lead to novel therapeutic targets in a wide range of renal diseases.

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          Most cited references 20

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          A Glu-496 to Ala polymorphism leads to loss of function of the human P2X7 receptor.

          The P2X(7) receptor is a ligand-gated cation-selective channel that mediates ATP-induced apoptosis of cells of the immune system. We and others have shown that P2X(7) is nonfunctional both in lymphocytes and monocytes from some subjects. To study a possible genetic basis we sequenced DNA coding for the carboxyl-terminal tail of P2X(7). In 9 of 45 normal subjects a heterozygous nucleotide substitution (1513A-->C) was found, whereas 1 subject carried the homozygous substitution that codes for glutamic acid to alanine at amino acid position 496. Surface expression of P2X(7) on lymphocytes was not affected by this E496A polymorphism, demonstrated both by confocal microscopy and immunofluorescent staining. Monocytes and lymphocytes from the E496A homozygote subject expressed nonfunctional receptor, whereas heterozygotes showed P2X(7) function that was half that of germline P2X(7). Results of transfection experiments showed that the mutant P2X(7) receptor was nonfunctional when expressed at low receptor density but regained function at a high receptor density. This density dependence of mutant P2X(7) function was also seen on differentiation of fresh monocytes to macrophages with interferon-gamma, which up-regulated mutant P2X(7) and partially restored its function. P2X(7)-mediated apoptosis of lymphocytes was impaired in homozygous mutant P2X(7) compared with germline (8.6 versus 35.2%). The data suggest that the glutamic acid at position 496 is required for optimal assembly of the P2X(7) receptor.
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            The P2Z purinoceptor: an intriguing role in immunity, inflammation and cell death.

             J F Virgilio (1995)
            Many immune and inflammatory cells express a plasma membrane receptor for extracellular ATP, termed the P2Z purinoceptor, which appears to be coupled to a plasma membrane pore. The physiological role of such a molecule is generally unknown, except for the striking susceptibility to ATP-mediated cytotoxicity that it confers. The receptor is upregulated in human monocytes by interferon gamma and is also expressed during macrophage differentiation. Here, Francesco Di Virgilio discusses recent information on this receptor, and suggests a possible role for it in the immune and inflammatory response.
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              Increased proliferation rate of lymphoid cells transfected with the P2X(7) ATP receptor.

              Human leukocytes can express the P2X(7) purinergic receptor, an ionic channel gated by extracellular ATP, for which the physiological role is only partially understood. Transfection of P2X(7) cDNA into lymphoid cells that lack this receptor sustains their proliferation in serum-free medium. Increased proliferation of serum-starved P2X(7) transfectants is abolished by the P2X(7) receptor blocker oxidized ATP or by the ATP hydrolase apyrase. Both wild type and P2X(7)-transfected lymphoid cells release large amounts of ATP into the culture medium. These data suggest the operation of an ATP-based autocrine/paracrine loop that supports lymphoid cell growth in the absence of serum-derived growth factors.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                September 2005
                30 May 2005
                : 101
                : 1
                : e24-e30
                aCentre for Nephrology & Department of Physiology, and bAutonomic Neuroscience Institute, Royal Free and University College Medical School, UCL, London, UK
                86036 Nephron Exp Nephrol 2005;101:e24–e30
                © 2005 S. Karger AG, Basel

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                Figures: 1, Tables: 1, References: 39, Pages: 1
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