Extracellular 2′,3′-cAMP and 3′,5′-cAMP stimulate proliferation of preglomerular vascular endothelial cells and renal epithelial cells

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Kidneys release into the extracellular compartment 3',5'-cAMP and its positional isomer 2',3'-cAMP. The purpose of the present study was to investigate the metabolism of extracellular 2',3'-cAMP and 3',5'-cAMP in preglomular vascular endothelial and proximal tubular epithelial cells and to determine whether these cAMPs and their downstream metabolites affect cellular proliferation. In preglomerular vascular endothelial and proximal tubular epithelial cells, 1) extracellular 2',3'-cAMP increased extracellular levels of 3'-AMP and 2'-AMP, whereas extracellular 3',5'-cAMP increased extracellular levels of 5'-AMP; 2) extracellular 5'-AMP, 3'-AMP, and 2'-AMP increased extracellular adenosine; 3) α,β-methylene-adenosine-5'-diphosphate (CD73 inhibitor) prevented the 5'-AMP-induced increase in extracellular adenosine in preglomerular vascular endothelial cells, but did not affect the 5'-AMP-induced increase in extracellular adenosine in proximal tubular cells or the 3'-AMP-induced or 2'-AMP-induced increase in extracellular adenosine in either cell type; 4) extracellular 2',3'-cAMP, 3'-AMP, 2'-AMP, 3',5'-cAMP, 5'-AMP, and adenosine stimulated proliferation of both preglomerular vascular endothelial and proximal tubular cells; and 5) MRS-1754 (selective A(2B) receptor antagonist) abolished the progrowth effects of extracellular 2',3'-cAMP, 3'-AMP, 2'-AMP, 3',5'-cAMP, 5'-AMP, and adenosine in both cell types. Extracellular 2',3'-cAMP and 3',5'-cAMP stimulate proliferation of preglomerular vascular endothelial cells and proximal tubular cells. The mechanism by which the cAMPs increase cell proliferation entails 1) metabolism to their respective AMPs, 2) metabolism of their respective AMPs to adenosine (which for 5'-AMP in preglomerular vascular endothelial cells is mediated by CD73), and 3) activation of A(2B) receptors. Both extracellular 2',3'-cAMP and 3',5'-cAMP may help restore architecture of the preglomerular microcirculation and tubular system following kidney injury.