Role of renal handling of extracellular nucleotides in modulation of phosphate transport

Abstract

The pivotal role of nucleotides in cell function and metabolism has been acknowledged for more than three decades since the milestone work of Sutherland [1]. Intracellular nucleotides are involved in each and every event of cell life including synthesis of nuclear material, phosphorylation processes, or transduction of extracellular signals. As regards to this last point, a huge number of studies has been devoted to identifying the key role of GTP-binding proteins or G proteins, on the one hand, and of cyclic nucleotides cAMP and cGMP, on the other hand, in the early steps of cell signaling. In epithelial cells such as renal tubular cells, generation of these mediators as a hallmark of cell-hormone interaction has been investigated in detail [reviewed in 2]. More recently, experimental evidence was provided showing that extracellular nucleotides are able to affect virtually every organ and/or tissue system. These aspects have been extensively reviewed [3—7] and will not be discussed here. Instead, attention will be focused on the effect of extracellular nucleotides, primarily cAMP, on renal tubular transport of inorganic phosphate (Pi). The initial observations that systemic infusion of cAMP to parathyroidectomized rats induced phosphaturia, thus mimicking the proximal effect of parathyroid hormone (PTH), drew attention on the effects of extracellular cAMP on renal function [8, 9]. A striking feature was that other renal effects of PTH (modulation of calcium or magnesium excretion), which take place beyond the proximal tubule, or renal effects of other peptidic hormones that act through the cAMP-protein kinase A pathway in distal parts of the nephron, such as antidiuteric hormone, were not reproduced by cAMP infusion [9]. Along the same line, glucagon, infused or injected at large pharmacological doses that induced a rise of plasma cAMP concentration from hepatic origin and urine excretion of the nucleotide [8, 10], was shown to increase phosphate excretion [8]. These data raised the possibility that handling (metabolism and/or transport) of extracellular cAMP by proximal cells was involved in the effect of the cyclic nucleotide on Pi transport. In contrast with the extreme experimental conditions described above, physiological situations are characterized by a fairly constant systemic cAMP concentration, while luminal cAMP concentration varies with the parathyroid status [10—12]. These observations suggest that luminal cAMP may act as local paracrine modulator of Pi transport and raise three questions: (a) How does cAMP reach the extracellular space under normal situations; (b)