Diadenosine polyphosphate-stimulated gluconeogenesis in isolated rat proximal tubules

Diadenosine polyphosphates released into the extracellular environment influence a variety of metabolic and other cellular activities in a wide range of target tissues. Here we have studied the impact of these novel nucleotides on gluconeogenesis in isolated rat proximal tubules. Gluconeogenesis was stimulated following exposure of isolated proximal tubules to a range of adenine-containing nucleotides including ADP, ATP, Ap(3)A, Ap(4)A, Ap(5)A and Ap(6)A. The concentration-dependence of ATP-, Ap(3)A- and Ap(4)A-mediated stimulation of gluconeogenesis was similar and was consistent with a role for these agents in the physiological control of renal metabolism. Nucleotide-stimulated gluconeogenesis was diminished in the presence of agents that interfere with phospholipase C activation or intracellular Ca2+ metabolism, indicative of a role for polyphosphoinositide-mediated Ca2+ mobilization in the mechanism of action of ATP, Ap(3)A and Ap(4)A. The characteristics of binding of [2-H-3]Ap(4)A to renal plasma-membrane preparations suggest that Ap(4)A mediates its effects on proximal tubule gluconeogenesis via interaction with P-2y-like purinoceptor(s) also recognized by extracellular ATP.