Abstract
Endogenously released adenosine-5’-triphosphate (ATP) is a key regulator of physiological function and inflammatory responses in the kidney. Genetic or pharmacological inhibition of purinergic receptors has been linked to attenuation of inflammatory disorders and hence constitutes promising new avenues for halting and reverting inflammatory renal diseases. However, the involvement of purinergic receptors in glomerulonephritis (GN) has only been incompletely mapped. Here, we demonstrate that induction of GN in an experimental antibody-mediated GN model results in a significant increase of urinary ATP-levels and an upregulation of P2Y2R expression in resident kidney cells as well as infiltrating leukocytes pointing toward a possible role of the ATP/P2Y2R-axis in glomerular disease initiation. In agreement, decreasing extracellular ATP-levels or inhibition of P2R during induction of antibody-mediated GN leads to a reduction in all cardinal features of GN such as proteinuria, glomerulosclerosis, and renal failure. The specific involvement of P2Y2R could be further substantiated by demonstrating the protective effect of the lack of P2Y2R in antibody-mediated GN. To systematically differentiate between the function of P2Y2R on resident renal cells versus infiltrating leukocytes, we performed bone marrow-chimera experiments revealing that P2Y2R on hematopoietic cells is the main driver of the ATP/P2Y2R-mediated disease progression in antibody-mediated GN. Thus, these data unravel an important pro-inflammatory role for P2Y2R in the pathogenesis of GN.
Highlights
Glomerulonephritis (GN) is an immunological disease and a major cause of dialysis-dependent end stage kidney disease
In order to elucidate the regulation of purinergic receptors in GN, we analyzed the expression of P2 receptor subtypes in whole murine kidney, isolated glomeruli, isolated podocytes, and “nonpodocytes” as well as in blood leukocytes
To assess the potential role of the P2Y2R in the pathogenesis of nephrotoxic serum (NTS)-GN, P2Y2 (−/−) mice were treated according to the NTS-driven model of GN
Summary
Glomerulonephritis (GN) is an immunological disease and a major cause of dialysis-dependent end stage kidney disease. Progressive glomerulonephritis (RPGN) is a subgroup of this entity, which is characterized by a rapid loss of renal function within days as well as proteinuria and glomerular hematuria. RPGN is associated with anti-glomerular basement membrane (GBM) antibodies or caused by other diseases such as ANCA associated vasculitis or IgA nephropathy. It represents one of the diagnostic and therapeutic emergencies in nephrology [1]. Current therapy is composed of intense immunosuppression using plasmapheresis, high-dose steroids, and cyclophosphamide, with frequent serious adverse effects and only limited renal survival [1]
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