The P2X7 receptor antagonist, oxidized adenosine triphosphate, ameliorates renal ischemia-reperfusion injury by expansion of regulatory T cells

Abstract

Extracellular adenosine triphosphate (ATP) binds to purinergic receptors and, as a danger molecule, promotes inflammatory responses. Here we tested whether periodate-oxidized ATP (oATP), a P2X7 receptor (P2X7R) antagonist can attenuate renal ischemia-reperfusion injury and clarify the related cellular mechanisms. Treatment with oATP prior to ischemia-reperfusion injury decreased blood urea nitrogen, serum creatinine, the tubular injury score, and tubular epithelial cell apoptosis after injury. The infiltration of dendritic cells, neutrophils, macrophages, CD69CD4, and CD44CD4 T cells was attenuated, but renal Foxp3CD4 Treg infiltration was increased by oATP. The levels of IL-6 and CCL2 were reduced in the oATP group. Additionally, oATP treatment following injury improved renal function, decreased the infiltration of innate and adaptive effector cells, and increased the renal infiltration of Foxp3CD4 Tregs. Post-ischemia-reperfusion injury oATP treatment increased tubular cell proliferation and reduced renal fibrosis. oATP treatment attenuated renal functional deterioration after ischemia-reperfusion injury in RAG-1 knockout mice; however, Treg depletion using PC61 abrogated the beneficial effects of oATP in wild-type mice. Furthermore, oATP treatment after transfer of Tregs from wild-type mice improved the beneficial effects of Tregs on ischemia-reperfusion injury, but treatment after transfer of Tregs from P2X7R knockout mice did not. Renal ischemia-reperfusion injury was also attenuated in P2X7R knockout mice. Experiments using bone marrow chimeras established that P2X7R expression on hematopoietic cells rather than non-hematopoietic cells, such as tubular epithelial cells, plays a major role in ischemia-reperfusion injury. Thus, oATP attenuated acute renal damage and facilitated renal recovery in ischemia-reperfusion injury by expansion of Tregs.

Therapeutic effect of berberine on renal ischemia-reperfusion injury in rats and its effect on Bax and Bcl-2

“…IRI is caused by blood flow perfusion after long-term organ ischemia, which can delay recovery of organ functions or even bring damages to tissues and organs (10). Reperfusion may also cause tissue damage, cell apoptosis and necrosis, which has great damage to the tissues and organs of patients (11).…”

Regulatory T cells in renal disease

“…77 Other interventions potentially mediated by modulating Tregs include a protective role for microRNA 26a (Mir-26a), which plays functional roles in cell differentiation, growth, apoptosis and metastasis, and modulates Th17/Treg balance, 78 and a P2X7 receptor antagonist, periodate-oxidised ATP (oATP). 79 As in other experimental models, in IRI IL-2/anti-IL-2 mAb complexes administered prior to IRI increased Tregs (in the spleen and kidney), resulting in less renal dysfunction and tubular injury, and when given after IRI, they promoted functional recovery and inhibited renal fibrosis. 80 As IL-2 and IL-33 promote the expansion of murine Tregs in vivo, Stremska et al generated an IL-2 and IL-33 fusion cytokine that they termed IL-233, and which they found increased the recruitment of Tregs into the kidney and protected mice from IRI more efficiently than either cytokine alone.…”

“…Transfer of human‐umbilical cord blood‐derived MSCs has similar effects . Other interventions potentially mediated by modulating Tregs include a protective role for microRNA 26a (Mir‐26a), which plays functional roles in cell differentiation, growth, apoptosis and metastasis, and modulates Th17/Treg balance, and a P2X7 receptor antagonist, periodate‐oxidised ATP (oATP) . As in other experimental models, in IRI IL‐2/anti‐IL‐2 mAb complexes administered prior to IRI increased Tregs (in the spleen and kidney), resulting in less renal dysfunction and tubular injury, and when given after IRI, they promoted functional recovery and inhibited renal fibrosis .…”

Extracellular nucleotide signaling in solid organ transplantation

“…On the other hand, deficiency of CD73 activity was shown to be beneficial in mild kidney IRI, suggesting a novel protective role for AMP‐mediated signaling . Koo et al demonstrated that a P2X7 receptor antagonist (or P2X7 receptor deficiency in hematopoietic cells) ameliorates murine renal IRI by expansion of regulatory T (Treg) cells. Similarly, apyrase treatment to degrade extracellular ATP protected mice from both acute and chronic renal IRI …”

“…On the other hand, deficiency of CD73 activity was shown to be beneficial in mild kidney IRI, suggesting a novel protective role for AMP-mediated signaling. 31 Koo et al 32 Outcomes from liver transplant have also been tied to adenine nucleotide levels and manipulation of ATP-mediated signaling.…”