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.

DPP-4 inhibition with alogliptin on top of angiotensin II type 1 receptor blockade ameliorates albuminuria <i>via</i> up-regulation of SDF-1α in type 2 diabetic patients with incipient nephropathy

“…It is well known that cAMP is abundantly produced in kidney [18]. In addition, estimated GFR values did not significantly alter by the switch from sitagliptin to alogliptin.…”

Modulation of bladder function by luminal adenosine turnover and A1receptor activation

“…Hence, the half-life of extracellular adenosine is kept short (seconds to minutes, depending on species) through the action of enzymes and transporters. This may be particularly important at the luminal surface of the bladder, which is not only a site of adenosine biosynthesis, but it is also impacted by adenosine produced by the kidney and present in the urine (25).…”

The 2′,3′-cAMP-adenosine pathway

“…We also tested whether isolated, perfused mouse kidneys express an extracellular 2=,3=-cAMP-adenosine pathway (51). In this regard, we administered into the renal artery 2=,3=-cAMP and 3=,5=-cAMP to isolated, perfused mouse kidneys and measured renal venous secretion rates of 2=,3=-cAMP, Fig.…”

“…What is known is that ecto-2=-AMPases and ecto-3=-AMPases are distinct from CD73 (also called ecto-5-nucleotidase) that functions as an ecto-5=-AMPase (i.e., converts extracellular 5=-AMP to adenosine). This conclusion is based on the observations that pharmacological inhibition of CD73 does not alter the metabolism of extracellular 2=-AMP and 3=-AMP to adenosine in PGVSMCs (53), GMCs (53), aortic vascular smooth muscle cells (52), coronary artery vascular smooth muscle cells (52), microglia (92) or astrocytes (92), and the metabolism of extracellular 2=,3=-cAMP to adenosine is similar in kidneys from CD73 knockout vs. wild-type mice (51).…”