Role of CD73 in Renal Sympathetic Neurotransmission in the Mouse Kidney.
Adenosine formed during renal sympathetic nerve stimulation (RSNS) enhances, by activating A1receptors, the postjunctional effects of released norepinephrine and participates in renal sympathetic neurotransmission. Because in many cell types CD73 (ecto-5'-nucleotidase) is important for the conversion of 5'-AMP to adenosine, we investigated whether CD73 is necessary for normal renal sympathetic neurotransmission. In isolated kidneys from CD73 wild-type mice (CD73 +/+; n=17) perfused at a constant rate with Tyrode's solution, RSNS increased perfusion pressure by 17±4, 36±8 and 44±10 mm Hg at 3, 5 and 7 Hz, respectively. Similar responses were elicited from kidneys isolated from CD73 knockout mice (CD73 -/-; n=13; 28±11, 43±10 and 44±10 mm Hg at 3, 5 and 7 Hz, respectively); and a high concentration (100 μmol/L) of α,β-methyleneadenosine 5'-diphosphate (CD73 inhibitor) did not alter responses to RSNS in C57BL/6 mouse kidneys (n=5; 21±5, 36±8 and 43±9 at 3, 5 and 7 Hz, respectively). Measurements of renal venous adenosine and inosine (adenosine metabolite) by liquid chromatography-tandem mass spectrometry demonstrated that the metabolism of exogenous 5'-AMP to adenosine and inosine was similar in CD73 -/- versus CD73 +/+ kidneys. A1receptor mRNA expression was increased in CD73 -/- kidneys, and 2-chloro-N6-cyclopentyladenosine (0.1 μmol/L; A1receptor agonist) enhanced renovascular responses to norepinephrine more in CD73 -/- versus CD73 +/+ kidneys. We conclude that CD73 is not essential for renal sympathetic neurotransmission because in the absence of renal CD73 other enzymes metabolize 5'-AMP to adenosine and because of compensatory upregulation of postjunctional coincident signaling between norepinephrine and adenosine.
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15219.
Edwin K
EK
Jackson
Dongmei
D
Cheng
Zaichuan
Z
Mi
Jonathan D
JD
Verrier
Keri
K
Janesko-Feldman
Patrick M
PM
Kochanek
5’-AMP; A1 Receptor; Adenosine; CD73; Ecto-5’-Nucleotidase; Norepinephrine; Renal Sympathetic Neurotransmission