In recent years it has become increasingly evident that purinoceptors, responsive to extracellular ATP and other nucleotides/nucleosides, are widely expressed in the kidney, both in the vasculature and the tubular epithelium. However, what they are doing there is far from clear. The present contribution will focus on P2 purinoceptors in the renal tubule; it will not consider vascular purinoceptors or tubular adenosine (P1) receptors. P2 receptors are of two broad types: P2X (mammalian sub-types 1-7), which are ionotropic, and P2Y (mammalian sub-types 1, 2, 4, 6, 11-13), which are metabotropic (G-coupled) receptors. Unfortunately, ‘mapping’ these sub-types along the nephron and identifying their actions has not been straightforward. Problems include species differences, the use of cell lines and cultures rather than native tissue, and poor specificity of agonists and antagonists.

The proximal tubule expresses mRNA for P2Y₁, P2Y₂, P2Y₄ and P2Y₆ receptors (Bailey et al. 2000, 2001a). Pharmacological characterisation (from the effects of basolaterally applied agonists on intracellular Ca²⁺ transients) suggests that the dominant sub-type in native tissue is P2Y₁, although there is functional evidence also for P2Y₂ and/or P2Y₄ and P2Y₆ receptors. Thus far, apical P2Y receptors have been identified only in cell lines. P2X₄ and P2X₅ mRNAs have been found in primary cultures of proximal tubule, but the situation in native tissue is unclear. Although a few unrelated actions of ATP on proximal tubules have been reported (e.g. stimulation of gluconeogenesis, attenuation of PTH-induced inhibition of phosphate transport), the physiological role, if any, of P2 receptors in this segment remains speculative.

Purinoceptor distribution in the loop of Henle is not fully characterised, but P2Y receptor mRNA expression has been identified in rat thin descending (P2Y₁, P2Y₂, P2Y₆), thin ascending (P2Y₁, P2Y₂, P2Y₄) and thick ascending (P2Y₁, P2Y₂, P2Y₄, P2Y₆) limbs (Bailey et al. 2000, 2001a). However, functional evidence is inconsistent: basolateral application of agonists in the rat elicits intracellular Ca²⁺ transients in thin, but not thick, limbs. To date, no information relating to apical P2 receptors in loop segments has been published, and no compelling evidence exists for nucleotide-induced physiological effects in the loop.

A somewhat clearer picture is beginning to emerge with respect to the distal nephron. There is evidence for P2Y₁, P2Y₂, P2Y₄, P2Y₆, P2X₅ and P2X₆ receptors in distal nephron segments, particularly the collecting duct – where some purinoceptors are located both basolaterally and apically (Schwiebert & Kishore, 2001). In vitro studies in perfused collecting ducts have shown that ATP applied variously to the basolateral or apical membrane can elicit intracellular Ca²⁺ transients and inhibit ENaC-mediated Na⁺ reabsorption (Lehrmann et al. 2002). Since in vitro findings may be viewed with some scepticism, we have recently examined the effect of luminal stimulation of P2 receptors in the intact collecting duct in vivo. We found that in rats on a normal diet, intraluminal application of the ATP analogue ATPλS had no effect on the urinary recovery of ²²Na that had been injected into the late distal tubule (Bailey et al. 2001b), whereas in rats on a low-Na⁺ diet, in which baseline ENaC-mediated Na⁺ reabsorption was enhanced, ATPλS caused a significant increase in ²²Na recovery (Shirley et al. 2001).

Finally, the possible role of purinoceptors in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) deserves mention. Cyst fluid contains high concentrations of ATP (Wilson et al. 1999), and ATP can stimulate Cl^– secretion in models of ADPKD (Schwiebert et al. 2002), suggesting that ATP plays a key role in cyst enlargement in this condition.

In summary, although investigations of purinoceptor function are hampered by the relative bluntness of the tools currently available, the release of nucleotides from tubular cells, together with the existence of receptors for them, argues for an autocrine/paracrine action. Only when sharper tools are brought to bear on the problem will the full contribution of renal purinoceptors to the control of Na⁺ excretion be revealed.

Work in the authors’ laboratory was supported by St Peter’s Trust for Kidney, Bladder & Prostate Research.