Extracellular cAMP-adenosine pathways in the mouse kidney

Abstract

The renal extracellular 2′,3′-cAMP-adenosine and 3′,5′-cAMP-adenosine pathways (extracellular cAMPs→AMPs→adenosine) may contribute to renal adenosine production. Because mouse kidneys provide opportunities to investigate renal adenosine production in genetically modified kidneys, it is important to determine whether mouse kidneys express these cAMP-adenosine pathways. We administered (renal artery) 2′,3′-cAMP and 3′,5′-cAMP to isolated, perfused mouse kidneys and measured renal venous secretion rates of 2′,3′-cAMP, 3′,5′-cAMP, 2′-AMP, 3′-AMP, 5′-AMP, adenosine, and inosine. Arterial infusions of 2′,3′-cAMP increased ( P < 0.0001) the mean venous secretion of 2′-AMP (390-fold), 3′-AMP (497-fold), adenosine (18-fold), and inosine (adenosine metabolite; 7-fold), but they did not alter 5′-AMP secretion. Infusions of 3′,5′-cAMP did not affect venous secretion of 2′-AMP or 3′-AMP, but they increased ( P < 0.0001) secretion of 5′-AMP (5-fold), adenosine (17-fold), and inosine (6-fold). Energy depletion (metabolic inhibitors) increased the secretion of 2′,3′-cAMP (8-fold, P = 0.0081), 2′-AMP (4-fold, P = 0.0028), 3′-AMP (4-fold, P = 0.0270), 5′-AMP (3-fold, P = 0.0662), adenosine (2-fold, P = 0.0317), and inosine (7-fold, P = 0.0071), but it did not increase 3′,5′-cAMP secretion. The 2′,3′-cAMP-adenosine pathway was quantitatively similar in CD73 −/− vs. +/+ kidneys. However, 3′,5′-cAMP induced a 6.7-fold greater increase in 5′-AMP, an attenuated increase (61% reduction) in inosine and a similar increase in adenosine in CD73 −/− vs. CD73 +/+ kidneys. In mouse kidneys, 1) 2′,3′-cAMP and 3′,5′-cAMP are metabolized to their corresponding AMPs, which are subsequently metabolized to adenosine; 2) energy depletion activates the 2′,3′-cAMP-adenosine, but not the 3′,5′-cAMP-adenosine, pathway; and 3) although CD73 is involved in the 3′,5′-AMP-adenosine pathway, alternative pathways of 5′-AMP metabolism and reduced metabolism of adenosine to inosine compensate for life-long deficiency of CD73.