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Am J Physiol Renal Physiol 292: F11-F14, 2007. First published August 29, 2006; doi:10.1152/ajprenal.00291.2006
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EDITORIAL FOCUS

Intraluminal autocrine purinergic signaling within cysts: implications for the progression of diseases that involve encapsulated cyst formation

Dragos Olteanu,1 Michael B. Hovater,1 and Erik M. Schwiebert1,2,3

Departments of 1Physiology and Biophysics, 2Cell Biology, and 3Recessive PKD Translational and Research Core Centers, University of Alabama at Birmingham, Birmingham, Alabama

PURINERGIC LIGANDS ARE LOCAL mediators, autacoids, or paracrine factors (5, 7–10, 12, 16, 47–49, 51, 63, 70). The role of extracellular nucleotides and nucleosides in physiology and pathophysiology has been studied for decades (5, 7–10, 12, 16). However, it was slow to be appreciated because of trepidations with regard to the loss of ATP as an intracellular biochemical fuel (9, 12, 16). Before the release of purinergic ligands from cells was studied extensively and systematically, multiple types of receptors for nucleotides (ATP, UTP, UDP, ADP, etc.) and nucleosides (adenosine, etc.) emerged from molecular cloning (1, 14, 27, 41, 49). The study of purinergic ligand's effects on cell function has exploded recently, as has the study of purinergic ligand release and the binding of these ligands to P2 (nucleotide) and P1 (nucleoside) receptors. A recently launched journal, Purinergic Signalling, speaks to this revolution (6).

With regard to purinergic signaling, it is now comprehensively appreciated that 1) all cells release ATP from small "releasable" pools that account for 0.1% or less of the total intracellular ATP content (up to 10 µM detectable secreted ATP from 5–10 mM total intracellular ATP) (1, 4, 5, 7–10, 12, 16, 47–50, 51, 61, 63, 70); 2) all cells express one or more subtypes of the ATP-gated P2X receptor channels, ATP-sensing P2Y G protein-coupled receptors, and adenosine-sensing P1 G protein-coupled receptors (1, 4, 5, 7–10, 12, 16, 26, 30, 33, 36, 47–50, 51, 56, 60, 62–64, 70, 74, 75); and 3) all cells are influenced by purinergic ligands via these receptors in similar and different ways (1, 4, 5, 7–10, 12, 16, 26, 30, 33, 36, 47–50, 51, 56, 60, 62–65, 70, 74, 75). An earlier article by Turner et al. (64) speaks directly to the concept of multiple P2Y and P2X receptors on the same cells in segments of the rat nephron. This paper, too, was a seminal and helpful study in the renal purinergic field. Purinergic agonists in vivo are not efficient as blood-borne mediators (5, 7–9, 12, 16, 47–51). ATP is degraded rapidly in the general circulation via multiple membrane-bound and secreted ecto-ATPases (5, 7–9, 12, 16, 47–51). Adenosine is recycled back into cells via nucleoside transporters to be used for ATP resynthesis (5, 7–9, 12, 16, 47–51). There is general agreement that purinergic ligand activity is short-lived and the ability of ATP or adenosine to bind to and signal via its many cell surface receptors is most robust in tissue "microenvironments." Such a concept has been reviewed elegantly by Burnstock (5, 7–9) and by Gordon (16); this concept is also being revisited in a series of minireviews to be published in a special issue of Purinergic Signalling in 2007 on the "Physiology of Nucleotide Release."

The current paper by Turner et al. (63), in this issue of the American Journal of Physiology-Renal Physiology, speaks directly to the concepts delineated above. In particular, it illustrates how important and robust purinergic ligands and their signal transduction systems are when cells and tissue remodel to form an ideal "purinergic signaling microenvironment" such as a cyst that is fully encapsulated and closed off from the rest of a tissue by a single monolayer of cyst-lining epithelial cells. In pathophysiological terms, the lumen of this encapsulated cyst becomes this ideal microenvironment. In a renal tubule or in a duct emanating from an endocrine gland (mammary tissue, ovary, etc.), the tubule or duct is an "open system," where the tubule fluid or glandular secretion enters one end and leaves the other. In an encapsulated cyst, solutes, ions, fluid, autocrine/paracrine ligands, etc. enter the lumen but they then become trapped. The creation of this abnormal yet robust microenvironment for autocrine and paracrine signaling within an encapsulated cyst is shown in Fig. 1.


Figure 1
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  		Fig. 1. Remodeling of a renal tubule or collecting duct along the nephron or in a secretory tissue into an encapsulated cyst creates an abnormal yet ideal autocrine purinergic signaling "microenvironment." A generic gland and duct structure within a breast, ovary, pancreas, secretory gland, etc. is shown (top left) as is a segment of the renal nephron (top right) showing the current model of how remodeling (top center) causes a fluid-filled cyst encapsulated by a single monolayer of cyst-lining epithelial cells (bottom left). Once fully encapsulated, robust nucleotide secretion and nucleoside accumulation (normally expelled out the duct to another tubule or duct lumen in an "open" system) becomes trapped in this "closed" system. Because multiple receptors are likely present in these cyst-lining cells for secreted nucleotides and nucleosides on the apical or luminal surface, a chronic autocrine loop for signaling will occur that continually draws salt and water into the cyst causing it to expand (see bottom center and bottom right). The "cross talk" and mitogenic effects are also illustrated (P2 and P1 purinergic receptors and growth factor receptors, bottom right). Either mechanism in a closed cystic system would become chronic, leading to volume expansion and cell proliferation within each cyst and its luminal microenvironment. CaCCs, calcium-activated Cl- channels.

 
Turner et al. (63) use a three-dimensional collagen gel culture system in which Madin-Darby canine kidney (MDCK) cells are seeded into this gel matrix as it forms. The cells organize into cyst structures and grow and expand in diameter and volume over time in vitro within this gel matrix. Turner et al. show elegantly and comprehensively that release of endogenous purinergic ligands into the microenvironment surrounding and within these MDCK cell cysts drives their growth and expansion. Use of apyrase, the ATP and ADP scavenger, as well as some nonspecific antagonists of P2 receptors inhibited cyst expansion markedly. Inhibitors of the ERK kinases slow cyst growth and expansion more dramatically. Both P2Y and P2X receptors can trigger ERK kinase activation (2, 37, 38), as can growth factor receptors (13). It is well known that purinergic receptor systems can "transactivate" growth factor receptor systems and cytokine receptor systems (14, 65). It is well known that purinergic ligands can act as mitogens in their own right or comitogens with growth factors (21, 26, 34, 42, 45, 46, 60, 63). As illustrated in the paper by Turner et al. (63) and discussed in the polycystic kidney disease (PKD) literature (11, 17, 57–59, 66–69), the interplay between local purinergic signaling and growth factor signaling may be critically important in the progression of PKD during remodeling and after cysts have formed. The monocilium of the ductal epithelium and the protein products of genes mutated in PKD may have a central galvanizing role in purinergic and growth factor signaling cross talk (15, 22–24, 31, 32, 39, 40, 43, 44, 71–73).

In past work, our laboratory showed that ATP content was robust in a subset of cyst fluid samples from autosomal dominant polycystic kidney disease (ADPKD) kidneys (70). We also showed that ADPKD cell monolayers released ATP across the apical membrane as or more readily than normal kidney cell monolayers (50, 70). This work was almost exclusively performed using primary cultures of human kidney cells grown as polarized cell monolayers. We also showed that multiple P2X and P2Y purinergic receptor subtypes were expressed by normal and ADPKD primary human cell monolayers and that nucleotide ligands to both types of P2 receptors could increase cell calcium and stimulate chloride secretion (50). Purinergic receptor-driven stimulation of chloride secretion has been well documented in MDCK cells as well as in other renal epithelial cell model systems from the collecting duct and in many other epithelial cell and tissue models (3, 11, 17, 20, 28–30, 33, 34–36, 50, 52–56, 74, 75). The CFTR chloride channel is often expressed in cyst-lining renal epithelial cells (20, 28, 29, 34, 35, 50, 52). It may also be detrimental in cyst fluid accumulation and expansion (11, 17, 20, 28, 29, 34, 35, 50, 52). Mouse models of ADPKD have yet to be crossed with mice with cystic fibrosis to test this hypothesis with mouse genetics. Purinergic receptor-driven rescue of lost chloride secretion is still being explored for possible therapeutic benefit in cystic fibrosis (30, 49, 56, 74, 75).

From this abundant work by us and others, we argued that autocrine and paracrine ATP and adenosine signaling could be detrimental to ADPKD cyst growth and expansion (11, 17, 20, 28, 29, 34, 35, 50, 52, 63). The detrimental pathophysiological effects could be the continual stimulation of chloride and fluid secretion into the encapsulated cysts (11, 17, 20, 28, 29, 34, 35, 50, 52, 63) and/or the chronic mitogenic effects on the cells that lined the encapsulated cysts (2, 11, 17, 21, 26, 34, 37, 38, 46–48, 50, 60, 63, 66–70). Not only could this be detrimental to the progression of ADPKD cysts in the kidney but it could also play a deleterious role in cysts observed in extrarenal tissues in ADPKD (11, 17) as well as in polycystic syndrome in other tissues such as ovary and breast (25) where P2Y and P2X receptors are also expressed. This being said, autocrine and paracrine purinergic signaling may play a very different role in autosomal recessive PKD (ARPKD), where encapsulated cysts rarely form and only dilation of renal collecting ducts and biliary duct is observed in the human condition (18, 19). ARPKD and ADPKD are very different diseases with respect to the type of tissue remodeling that occurs (17–19); this is an important caveat that needs to be voiced.

Our laboratory is extremely excited about the work of Unwin and colleagues (63, 64) because the current paper (63) has clearly reawakened the concepts that autocrine and paracrine purinergic and growth factor signaling may indeed be detrimental to the progression of cystic diseases during the remodeling of tissue and after formation of encapsulated cysts has occurred. It is our hope that the ADPKD research community applies these findings to collagen gel studies of primary human ADPKD cell cysts or to kidney organ culture models where cyst formation can be visualized. In these models, it is also highly likely that antagonism of local purinergic signaling may slow cyst progression and that existing as well as novel therapeutics may be brought to bear on ADPKD pathogenesis.


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We acknowledge the support of National Institute of Diabetes and Digestive and Kidney Diseases Grants R01-DK-067343 (to E. M. Schweibert) and DK-074038 (to the P30 Recessive PKD Research and Translation Core Centers). We also acknowledge the support of the Department of Physiology and Biophysics, University of Alabama at Birmingham, for the stipend and benefits for M. B. Hovater.


   FOOTNOTES
 

Address for reprint requests and other correspondence: E. M. Schwiebert, Dept. of Physiology and Biophysics and of Cell Biology, Univ. of Alabama at Birmingham, MCLM 740, 1918 Univ. Blvd., Birmingham, AL 35294-0005 (e-mail: eschwiebert{at}physiology.uab.edu)


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