Effects and Mechanism of 2′-AMP on Renal Vascular Resistance

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KEY POINTS: 2'-AMP is endogenous and causes renal vasoconstriction in part by allosteric modulation of P2X1 receptors that enhances ATP-induced opening of P2X1 receptor channels. Kidney tissue nonspecific alkaline phosphatase (TNAP) by metabolizing 2'-AMP protects against 2'-AMP-induced renal vasoconstriction, a protection lost when kidney TNAP activity is reduced. Drugs with off-target effects that reduce kidney TNAP activity should be avoided in patients at risk of kidney injury. BACKGROUND: Knockout of 2',3'-cyclic-nucleotide 3'-phosphodiesterse (an enzyme that converts 2',3'-cAMP to 2'-AMP) reduces 2'-AMP production and improves renal perfusion in renal ischemia-reperfusion injury (R-IRI). These findings motivated our hypothesis, herein tested, that 2'-AMP causes renal vasoconstriction. METHODS: The effect of 2'-AMP on renal vascular resistance (RVR) was investigated in rat kidneys, both in vitro and in vivo . 2'-AMP interactions with P2X1 receptors (P2X1Rs) were investigated in membrane preparations and HEK cells. Urinary 2'-AMP levels were assessed in cardiac surgery/cardiopulmonary bypass (CS-CPB) patients using mass spectrometry. RESULTS: In vitro , intra-renal-artery-infused 2'-AMP was rapidly metabolized to adenosine and did not increase RVR. Coadministration of a tissue nonspecific alkaline phosphatase inhibitor (TNAPI) reduced 2'-AMP metabolism, thus enabling 2'-AMP to trigger renal vasoconstriction. In vivo , kidneys rapidly metabolized intra-renal-artery-infused 2'-AMP to adenosine; this was blocked with a TNAPI. In vivo , intra-renal-artery-infused 2'-AMP decreased RVR, as did adenosine. By contrast, when coadministered with a TNAPI, 2'-AMP increased RVR, and this response was inhibited by NF449 (P2X1R antagonist). In membranes, 2'-AMP enhanced 3 H- αβ -methylene-ATP (P2X1R agonist) binding to P2X1Rs, and in HEK cells, 2'-AMP doubled αβ -methylene-ATP-induced (and P2X1R-mediated) calcium influx. In TNAPI+2'-AMP-pretreated, but not naïve, rats, βγ -methylene-ATP (P2X1R agonist) caused renal vasoconstriction. In rats, R-IRI reduced kidney tissue nonspecific alkaline phosphatase (TNAP) activity, and TNAP inhibition worsened R-IRI. In CS-CPB patients, urinary 2'-AMP levels were elevated 169% during CS-CPB and were associated with a 45% increase in peak 24-hour postprocedure serum creatinine. CONCLUSIONS: 2'-AMP is a renal vasoconstrictor; however, TNAP, by metabolizing 2'-AMP to adenosine, protects against 2'-AMP-induced renal vasoconstriction. This protection is lost when TNAP activity is reduced. 2'-AMP-induced renal vasoconstriction involves positive allosteric modulation of P2X1Rs that enhances ATP-induced opening of P2X1R channels. R-IRI reduces kidney TNAP activity, and TNAP inhibition worsens R-IRI outcomes.

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