POINT-COUNTERPOINT
ATP mediates tubuloglomerular feedback

Department of Physiology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112-2699

	ARTICLE

TOP ARTICLE REFERENCES

THE MACULA DENSA CELLS COMPRISE the sensing component of the tubuloglomerular feedback (TGF) mechanism and respond to changes in tubular fluid composition by transmitting signals to the afferent arterioles thus regulating the preglomerular vascular resistance and filtered load to the tubules (14, 15). This intriguing mechanism has remained under intensive investigation, and the accrued evidence indicates that there are multiple interacting paracrine agents involved in the communication pathway between the macula densa cells and the vascular smooth muscle cells. The macula densa cells are thought to produce and release ATP, adenosine, arachidonic acid metabolites, and nitric oxide. Some of these serve to modulate the sensitivity of the TGF mechanism, and it has remained a formidable challenge to discriminate between the powerful modulators and the specific mediator that respond to the acute changes in distal tubular fluid composition. Perhaps the single most important criterion distinguishing between the mediator and modulators is that there should be a direct relationship between the change in the macula densa stimulus and the change in the release or concentration of the TGF mediator associated with the change in renal vascular resistance (RVR).

Because the TGF mechanism participates in the autoregulatory responses of the arteriolar vasculature to changes in perfusion pressure, it is also recognized that the mediator of the TGF mechanism contributes to the changes in RVR associated with autoregulatory responses (15, 20, 22). Thus one would expect a certain internal consistency in the evidence regarding the mechanism that mediates the TGF mechanism and the mechanism that mediates autoregulatory responses. Considering that the TGF mechanism is a major mediator of renal autoregulatory responses and primarily serves to regulate afferent arteriolar resistance (9, 15, 20), it is surprising that no consensus has emerged regarding the nature of the signaling mechanism that links macula densa function with the changes in afferent arteriolar resistance. Nevertheless, analysis of the available data provides strong support for the hypothesis that ATP, rather than adenosine, serves as the actual mediator of TGF mechanism. Our analysis is based on the following criteria.

Criterion 1. The TGF mediator must exert selective actions on preglomerular arterioles (15) to stimulate Ca²⁺ influx in afferent arteriolar renal vascular smooth muscle cells via activation of L-type voltage-dependent Ca²⁺ channels in the afferent arterioles (5, 15).

Criterion 2. Saturation of the renal interstitial fluid (RIF) with the TGF mediator would interfere with the ability of the afferent arteriolar smooth muscle cells to respond to either TGF or autoregulatory responses.

Criterion 3. Blockade of the vascular smooth muscle receptors that respond to the TGF mediator would also interfere with TGF and autoregulatory responses.

Criterion 4. The mediator must be released from macula densa cells into the renal interstitium to exert its actions on the afferent arteriolar vascular smooth muscle cells. Furthermore, there should be a relationship between changes in TGF or autoregulation dependent alterations in RVR and the interstitial fluid concentration of the mediator.

Point 1. ATP selectively constricts the afferent arterioles. Studies using the juxtamedullary nephron preparation demonstrated that ATP exerts direct sustained vasoconstrictive actions on afferent, but not efferent, arterioles (5, 9, 11). Furthermore, autoradiographic and immunohistochemical experiments demonstrated that the preglomerular renal vasculature expresses abundant P2_X receptors, whereas efferent arterioles appear to be devoid of such receptors (3, 4).

Point 2. ATP increases Ca²⁺ influx into renal microvascular smooth muscle cells. ATP and P2_X agonists, such as ,-methylene-ATP, activate Ca²⁺ influx pathways in freshly isolated vascular smooth muscle cells obtained from preglomerular microvessels (5, 6). These actions of ATP and of slowly metabolizable analogs of ATP are sensitive to blockade of L-type calcium channels (5, 10).

Point 3. Autoregulatory-mediated afferent arteriolar vasoconstrictor responses are prevented by P2 receptor saturation or desensitization (8). Micropuncture and microperfusion experiments demonstrated that stop-flow pressure TGF responses to increases in late proximal perfusion rate are markedly blunted during peritubular capillary infusion with saturating doses of ATP or slowly metabolizable analogs (9, 13). P2 receptor saturation at the whole kidney level by intrarenal arterial infusion of high doses with ATP resulted in marked impairment of renal blood flow and glomerular filtration rate autoregulatory efficiency (12).

Point 4. P2 receptor blockade blocks afferent arteriolar autoregulatory responses. Suramin and pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (8) and a more selective P2_X receptor antagonist, NF-279 (7), have all been shown to prevent afferent arteriolar autoregulatory responses to increases in perfusion pressure.

Point 5. Macula densa cells secrete ATP. Although the macula densa cells have abundant mitochondria, they have reduced levels of Na⁺-K⁺-ATPase, making the macula densa cells good candidates for a source of extracellular ATP (18). Recent studies by Bell et al. (1) demonstrated that the macula densa cells have a maxi-Cl channel that is permeable to ATP and that increases in luminal NaCl concentrations result in the release of ATP from macula densa cells.

Point 6. RIF concentrations of ATP are closely associated with autoregulatory TGF-mediated changes in RVR. With the use of microdialysis probes, the RIF ATP concentrations were shown to decrease consistently in response to reductions in renal arterial pressure. Furthermore, there was a highly significant relationship between RIF ATP and autoregulatory associated alterations in RVR (16, 17). Whole kidney stimulation of the TGF mechanism elicited by administration of a carbonic anhydrase inhibitor, acetazolamide, to inhibit proximal reabsorption rate and increase distal volume delivery (20, 21) led to increases in RIF ATP concentrations, whereas furosemide treatment reduced RIF ATP concentrations (16, 17). The association between the autoregulatory adjustments in RVR and RIF ATP concentrations is enhanced after treatment with acetazolamide, whereas furosemide abolished the relationship between RVR and RIF ATP (17).

	ACKNOWLEDGEMENTS

The work performed in the authors' laboratory was supported by National Heart, Lung, and Blood Institute Grant HL-18426 and from the American Heart Association, Southeast Affiliate (to A. Nishiyama).

	FOOTNOTES

Present address for A. Nishiyama: Department of Pharmacology, Kagawa Medical University, 1750-1 Ikenobe, Miki-Cho, Kita-Gun, Kagawa 761-0793, Japan (akira{at}kms.ac.jp).

Address for reprint requests and other correspondence: L. G. Navar, Dept. of Physiology, #SL-39, Tulane Univ. Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112-2699 (E-mail: navar{at}tulane.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

10.1152/ajpregu.00071.2002

	REFERENCES

TOP ARTICLE REFERENCES

1.   Bell, PD, Lapointe JY, Sabirov R, Hayashi S, and Okada Y. Maxi-chloride channel in macula densa cells: possible pathway for ATP release (Abstract). FASEB J 14: A134, 2001.

2.   Brown, R, Ollerstam A, Johansson B, Skott O, Gebre-Medhin S, Fredholm B, and Persson AE. Abolished tubuloglomerular feedback and increased plasma renin in adenosine A₁ receptor-deficient mice. Am J Physiol Regulatory Integrative Comp Physiol 281: R1362-R1367, 2001[Abstract/Free Full Text].

3.   Chan, CM, Unwin RJ, Bardini M, Oglesby IB, Ford AP, Townsend-Nicholson A, and Burnstock G. Localization of P2X1 purinoceptors by autoradiography and immunohistochemistry in rat kidneys. Am J Physiol Renal Physiol 274: F799-F804, 1998[Abstract/Free Full Text].

4.   Chan, CM, Unwin RJ, and Burnstock G. Potential functional roles of extracellular ATP in kidney and urinary tract. Exp Nephrol 6: 200-207, 1998[ISI][Medline].

5.   Inscho, EW. P2 receptors in regulation of renal microvascular function. Am J Physiol Renal Physiol 280: F927-F944, 2001[Abstract/Free Full Text].

6.   Inscho, EW, Belott TP, Mason MJ, Smith JB, and Navar LG. Extracellular ATP increases cytosolic calcium in cultured rat renal arterial smooth muscle cells. Clin Exp Pharmacol Physiol 23: 503-507, 1996[ISI][Medline].

7.   Inscho, EW, and Cook AK. P2_X1 receptor blockade inhibits pressure-induced afferent arteriolar autoregulatory behavior (Abstract). Hypertension 36: 682, 2001.

8.   Inscho, EW, Cook AK, and Navar LG. Pressure-mediated vasoconstriction of juxtamedullary afferent arterioles involves P2-purinoceptor activation. Am J Physiol Renal Fluid Electrolyte Physiol 271: F1077-F1085, 1996[Abstract/Free Full Text].

9.   Inscho, EW, Mitchell KD, and Navar LG. Extracellular ATP in the regulation of renal microvascular function. FASEB J 8: 319-328, 1994[Abstract].

10.   Inscho, EW, Ohishi K, Cook AK, Belott TP, and Navar LG. Calcium activation mechanisms in the renal microvascular response to extracellular ATP. Am J Physiol Renal Fluid Electrolyte Physiol 268: F876-F884, 1995[Abstract/Free Full Text].

11.   Inscho, EW, Ohishi K, and Navar LG. Effects of ATP on pre- and postglomerular juxtamedullary microvasculature. Am J Physiol Renal Fluid Electrolyte Physiol 263: F886-F893, 1992[Abstract/Free Full Text].

12.   Majid, DSA, Inscho EW, and Navar LG. P2 purinoceptor saturation by adenosine triphosphate impairs renal autoregulation in dogs. J Am Soc Nephrol 10: 492-498, 1999[Abstract/Free Full Text].

13.   Mitchell, KD, and Navar LG. Modulation of tubuloglomerular feedback responsiveness by extracellular ATP. Am J Physiol Renal Fluid Electrolyte Physiol 264: F458-F466, 1993[Abstract/Free Full Text].

14.   Navar, LG. Integrating multiple paracrine regulators of renal microvascular dynamics. Am J Physiol Renal Physiol 274: F433-F444, 1998[Abstract/Free Full Text].

15.   Navar, LG, Inscho EW, Majid DSA, Imig JD, Harrison-Bernard LM, and Mitchell KD. Paracrine regulation of the renal microcirculation. Physiol Rev 76: 425-536, 1996[Abstract/Free Full Text].

16.   Nishiyama, A, Majid DSA, Taher KA, Miyatake A, and Navar LG. Relation between renal interstitial ATP concentrations and autoregulation-mediated changes in renal vascular resistance. Circ Res 86: 656-662, 2000[Abstract/Free Full Text].

17.   Nishiyama, A, Majid DSA, Walker M, III, Miyatake A, and Navar LG. Renal interstitial ATP responses to changes in arterial pressure during alterations in tubuloglomerular feedback activity. Hypertension 37: 753-759, 2001[Abstract/Free Full Text].

18.   Schnermann, J, and Marver D. ATPase activity in macula densa cells of the rabbit kidney. Pflügers Arch 407: 82-86, 1986[ISI][Medline].

19.   Sun, D, Samuelson LC, Yang T, Huang Y, Paliege A, Saunders T, Briggs J, and Schnermann J. Mediation of tubuloglomerular feedback by adenosine: evidence from mice lacking adenosine 1 receptors. Proc Natl Acad Sci USA 98: 9983-9988, 2001[Abstract/Free Full Text].

20.   Walker, M, III, Harrison-Bernard LM, Cook AC, and Navar LG. Dynamic interaction between myogenic and TGF mechanisms in afferent arteriolar blood flow autoregulation. Am J Physiol Renal Physiol 279: F858-F865, 2000[Abstract/Free Full Text].

21.   Walker, M, III, Nishiyama A, Majid DSA, Taher KA, and Navar LG. Dynamic autoregulatory interactions between tubuloglomerular feedback and myogenic mechanisms controlling blood flow in canine kidneys (Abstract). FASEB J 14: A134, 2000.