Purinoceptor regulation of renal tubular transport is coming of age.

THE KIDNEY PLAYS a central role in regulating blood pressure, body fluid volume, body fluid composition, and electrolyte and water balance. Generations of effort have gone into understanding the tubular and vascular interactions that confer incredible fidelity in accomplishing these essential functions. While P2 purinergic signaling systems were investigated in other organ systems for some time, the role P2 receptors play in influencing renal vascular and tubular function did not really begin to develop until about 1990. Since then, investigators have provided considerable evidence that P2 receptors are involved in many aspects of renal vascular and tubular physiology. ATP is released by renal tissues (13, 14, 27) including macula densa (3, 10), loop of Henle (22, 24), cortical collecting duct (6), and probably proximal tubule (26). In each of these tubular segments, physiologic control of renal transport mechanisms is implicated, but the specific mechanisms by which that regulation occurs are not completely understood. The current report from Silva and Garvin (22a) now advances the role of ATP and P2 receptor activation in regulating tubular function in the thick ascending loop of Henle. Aside from the important roles P2 receptors play in regulating microvascular autoregulatory function (5), P2 receptors are widely expressed by tubular epithelial cells (19, 23, 25). Detection of ATP release by renal epithelial cells spurred interest in the possibility that tubular transport function could be under purinergic control (11, 19, 25, 30). There is compelling evidence that locally released ATP exerts autocrine control of epithelial sodium channel (ENaC) activity in the apical membrane of mouse cortical collecting duct cells (16, 20, 25, 29). Data indicate that ATP-dependent suppression of apical ENaC activity involves P2Y2 receptor activation (and possibly other P2 receptor subtypes) coupled to phospholipase C activation (28, 29). Thus, modulation of ENaC activity represents a potentially important mechanism for purinoceptor-dependent regulation of collecting duct transport function. Kishore and colleagues (8) and Rouse et al. (18) demonstrated that ATP, and the P2Y2 agonist UTP, reduces osmotic water permeability, thus limiting antidiuretic hormone-dependent water reabsorption. Therefore, local ATP action in the collecting duct can influence tubular transport function. Macula densa cells release ATP in response to increased luminal NaCl concentration or dietary salt intake (10). Basolateral release of ATP appears linked to apical transport of NaCl via the Na -K -2Cl cotransporter and serves to evoke tubuloglomerular feedback-mediated vasoconstriction of the afferent arteriole (3, 9, 10). This mechanism provides an important autoregulatory influence on afferent arteriolar resistance (5). In the rat proximal tubule, activation of apical P2Y1 receptors reduces bicarbonate reabsorption through inhibition of Na /H exchange activity, presumably involving suppression of NHE3, specifically (1). ATP, UTP, and ATP-S stimulate gluconeogenesis in freshly prepared rat proximal tubules suggesting a Ca -dependent regulation of gluconeogenesis by P2Y2 receptor activation (4, 12). The rat distal convoluted tubule expresses several P2X and P2Y receptor subtypes (23). Activation of these receptors by ATP stimulates an increase in cytosolic Ca (2), but the physiological functions of P2 receptors in this nephron segment remain to be defined. The current report (22a) provides novel information demonstrating a physiological role for ATP-mediated regulation of transport function in the loop of Henle, one of the remaining tubular segments for which P2 receptor-dependent regulation of transport function has not been demonstrated. Along the loop of Henle essentially nothing is known about P2 receptormediated regulation of transport function except that P2 receptor expression and P2 receptor-mediated Ca signaling responses are documented (2, 25). The thick ascending loop of Henle contributes a significant portion of total renal Na reabsorption but little is known about how P2 receptors influence that role. Silva and colleagues provide unique insights that integrate with other reports and begin forming a coherent set of events that influence loop transport function. Prior work by Garvin’s group and others (17, 21, 22, 25) indirectly implicated P2 receptor activation with suppression of Na transport. Recent work indicated that modulation of luminal flow stimulated apical and basolateral release of ATP from perfused mouse thick ascending limb tubules that produced P2Y2 receptor-dependent increases in cytosolic Ca concentration (7). Reducing tubular fluid tonicity also stimulated ATP release from rat thick ascending loop tubules and this release was linked to activation of TRPV4 channels (22). P2Y2 receptordeficient mice exhibited increased expression of the Na -K 2Cl cotransporter and increased sensitivity to furosemide (17). Garvin and colleagues (21) produced a series of reports indicating that ATP stimulates nitric oxide production in thick ascending limbs and that nitric oxide inhibits thick ascending limb Na transport by inhibiting Na -K -2Cl cotransporter activity (15). Extracellular ATP stimulates nitric oxide production apparently by activating a P2X receptor subtype (21); however, P2Y receptors could also be involved. These data support the postulate that the loop of Henle is under local autocrine/paracrine purinergic control to regulate solute transport. This regulation involves many metabolically linked signaling pathways that should result in decreased oxygen consumption in the wake of driving the ATP release mechanisms and transport mechanisms. In the current report, Drs. Silva and Garvin (22a) begin to tie together these independent observations by demonstrating that extracellular ATP inhibits oxygen consumption by inhibiting Na reabsorption in the thick ascending loop of Henle. This decrease in transport activity reflects reduced Na entry across the apical membrane, rather than reduced Na -K -ATPase activity at the basolateral membrane. Suppression of Na reabsorption by ATP arises from Address for reprint requests and other correspondence: E. W. Inscho, Dept. of Physiology, CA-3137, Medical College of Georgia, 1120 15th Str., Augusta, GA 30912 (e-mail: [email protected]). Am J Physiol Renal Physiol 297: F1166–F1167, 2009; doi:10.1152/ajprenal.00506.2009.