The role of P2X7 receptors in intrinsic renal cells

Abstract

Glomerulonephritis is a primary cause of end stage renal disease and current therapy involves relatively non-specific high-dose immunosuppression that can have serious side effects. Previously, the importance of the NLRP3-inflammasome and its associated cytokines, IL-1 and IL-18, were demonstrated in a number of experimental glomerulonephritis models, where their deficiency or pharmacological blockade proved beneficial in reducing inflammation and renal cell apoptosis. Whilst the role of P2X7R in the activation of the canonical NLRP3-inflammasome pathway is well established in immune cells, it remains controversial whether P2X7R is expressed and functional on intrinsic renal cells. Here, I show that levels of IL-18 are significantly augmented in the circulation of patients with IgA Nephropathy (IgAN), ANCA-vasculitis (AAV) and membranous nephropathy (MN). My studies suggest that in IgAN the primary source of this cytokine may be renal, whereas, in AAV it may be largely systemic. Furthermore, I demonstrated that renal cell-derived IL-18 may be released in a P2X7R-independent manner as at steady state intrinsic renal cells express, and in response to inflammatory stimuli can upregulate non-large pore forming surface P2X7Rs.

The human P2X7R has multiple splice variants (P2X7RA-J). However, only two (P2X7RB and P2X7RJ) are thought to be translated. Both have been demonstrated to regulate full-length receptor function. I hypothesised that renal cell non-large pore forming P2X7Rs may be due to the expression of these variants. Accordingly, my results showed that intrinsic renal cells express all identified P2X7R splice variants. Additionally, I demonstrated for the first time that the previously undescribed P2X7RE variant can also be expressed as a mature protein. Moreover, my studies revealed that P2X7RE and P2XRJ are differentially expressed on PBMCs from IgAN and AAV patients compared to healthy controls, potentially leading to overactivated P2X7R in the periphery of AAV patients.