Booth, JWR; (2014) An investigation of the role of the P2X7 purinoceptor in the pathogenesis of diabetic nephropathy. Doctoral thesis (PhD), UCL (University College London).

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Abstract

P2X7 is a member of the P2X purinoceptor family and functions as an ATP-gated non-selective cation channel. Expression is greatest in cells of the immune system where it plays a key role in the orchestration of IL1β maturation and release. Diabetic nephropathy (DN) is traditionally considered a ‘metabolic’ disease, but is increasingly recognized to have an important inflammatory component. The work in this thesis tests the hypothesis that P2X7 contributes to the pathogenesis of DN and, in particular, development of renal inflammation in this disease. P2X7 expression was examined by immunohistochemistry in human kidney biopsy tissue; glomerular expression was identified in a subset of patients with early clinical DN. P2X7 expression was also upregulated at 12 weeks in glomeruli of rodents with both type 1 and type 2 diabetes. After induction of diabetes with low-dose STZ, GSK P2X7 KO mice exhibited a marked reduction in glomerular macrophage infiltration compared to WT, without impact on albuminuria or serum creatinine. A trend towards protection against induction of diabetes was also apparent in GSK KO mice; this protection was more pronounced in the Pfizer P2X7 KO strain and accompanied by reduced islet macrophage infiltration and preservation of β-cell mass. The mechanism linking P2X7 and glomerular macrophage infiltration was explored in vitro. A selective P2X7 antagonist, A438079, partially abrogated hyperglycaemia-induced secretion of the macrophage chemokine, MCP-1, from primary human mesangial cells (pHMC). MCP-1 secretion was enhanced by the ATP-hydrolysing agent, apyrase, as well as by application of 5-BDBD, a selective P2X4 antagonist, suggesting chemokine secretion from pHMCs may be modulated by competing purinoceptor signals. In summary, P2X7 is upregulated at an early time-point in rodent diabetic glomeruli, and contributes to glomerular and pancreatic inflammation in murine experimental disease. Comparable upregulation of P2X7 observed in human glomeruli in DN bodes well for future translational studies.

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