Diadenosine polyphosphate-stimulated gluconeogenesis in isolated rat proximal tubules

Abstract

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, Ap3A, Ap4A, Ap5A and Ap6A. The concentration-dependence of ATP-, Ap3A- and Ap4A-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, Ap3A and Ap4A. The characteristics of binding of [2-3H]Ap4A to renal plasma-membrane preparations suggest that Ap4A mediates its effects on proximal tubule gluconeogenesis via interaction with P2y-like purinoceptor(s) also recognized by extracellular ATP.

Uridine nucleotide-induced stimulation of gluconeogenesis in isolated rat proximal tubules

“…The basal, lactate-supported glucose production was similar to that observed previously by ourselves (Askin et al 1990) and other workers (Cha et al 1995), thereby confirming the metabolic viability of the tubule preparations. Exogenous ATP provoked an approximately 50% stimulation of the lactate-supported gluconeogenic rate, essentially similar to that previously reported (Edgecombe et al 1997). This stimulation of gluconeogenesis is also similar to that caused by Ca 2+ -mobilizing hormones (e.g.…”

“…Biochemicals and reagents were obtained from the sources described previously (Edgecombe et al 1997) with the following additions. Uridine nucleotides, GTPγS, neomycin, nifedipine, reactive blue 2 and nucleotide diphosphate kinase were from Sigma.…”

“…This renal gluconeogenic activity appears to be restricted to the proximal tubules (Guder and Ross 1984). In the rat, renal gluconeogenesis is sensitive to hormones (McDonald and Saggerson 1977;Richardson et al 1993) and extracellular adenine nucleotides (Cha et al 1995;Edgecombe et al 1997;Saggerson et al 1983). Adenine nucleotides, presumably acting through P2Y 1 -and P2Y 2 -purinoceptors, bring about Ca 2+ -mediated stimulation of gluconeogenesis in proximal tubular cells.…”

Potential Functional Roles of Extracellular ATP in Kidney and Urinary Tract

“…Since volume regulation is particularly important in polarized and transporting epithelia, this finding may also be relevant to renal tubular cells. Finally, very recent studies on isolated renal proximal tubular cells in culture have demonstrated a putative apical membrane P2Y 2 -mediated inhibition of the basolateral Na + -K + -ATPase, which is independent of a change in cytosolic calcium [40], and another has found a P2Y-linked stimulation of gluconeogenesis [45]. …”

Aminoacyl tRNA synthetases and their connections to disease

“…Thus, the catalytic activities for glycyl-, lysyl-, and tryptophanyl-tRNA synthetase have been adapted to synthesize diadenosine polyphosphates (Ap n A), which are believed to regulate glucose metabolism (1,2), cell proliferation, and death (3). Similarly, the tRNA recognition capacity of bacterial threonyl-and human glutamylprolyl-tRNA synthetases has been adapted for regulating translation by interacting with the 5Ј (4) and 3Ј UTR regions (5) of gene-specific transcripts.…”