Autocrine extracellular purinergic signaling in epithelial cells derived from polycystic kidneys

Schwiebert, Erik M.; Wallace, Darren P.; Braunstein, Gavin M.; King, Sandi R.; Peti‐Peterdi, Janos; Hanaoka, Kazushige; Guggino, William B.; Guay‐Woodford, Lisa M.; Bell, P. Darwin; Sullivan, Lawrence P.; Grantham, Jared J.; Taylor, A. M. Robert

doi:10.1152/ajprenal.0337.2000

Cited by 117 publications

(156 citation statements)

References 52 publications

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“…In fact, ATP release and signaling is increased in PKD cell culture systems (Schwiebert and Zsembery, 2003). ATP and the PC-1 C termini have been shown to regulate chloride secretion and cyst growth in ADPKD (Wilson et al, 1999;Schwiebert et al, 2002;Hooper et al, 2003). Dysregulation of ATP synthase activity at the cell surface in ADPKD cysts may result in increases in ATP release and inappropriate chloride channel or purinergic receptor activation.…”

Section: Discussionmentioning

confidence: 99%

ATP-2 Interacts with the PLAT Domain of LOV-1 and Is Involved inCaenorhabditis elegansPolycystin Signaling

Barr

2005

MBoC

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Caenorhabditis elegans is a powerful model to study the molecular basis of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is caused by mutations in the polycystic kidney disease (PKD)1 or PKD2 gene, encoding polycystin (PC)-1 or PC-2, respectively. The C. elegans polycystins LOV-1 and PKD-2 are required for male mating behaviors and are localized to sensory cilia. The function of the evolutionarily conserved polycystin/lipoxygenase/␣-toxin (PLAT) domain found in all PC-1 family members remains an enigma. Here, we report that ATP-2, the ␤ subunit of the ATP synthase, physically associates with the LOV-1 PLAT domain and that this interaction is evolutionarily conserved. In addition to the expected mitochondria localization, ATP-2 and other ATP synthase components colocalize with LOV-1 and PKD-2 in cilia. Disrupting the function of the ATP synthase or overexpression of atp-2 results in a male mating behavior defect. We further show that atp-2, lov-1, and pkd-2 act in the same molecular pathway. We propose that the ciliary localized ATP synthase may play a previously unsuspected role in polycystin signaling. INTRODUCTIONAutosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic diseases, affecting one per 400-1000 individuals (Igarashi and Somlo, 2002). This syndrome is characterized by progressive development of fluid-filled, epithelial cysts in the kidney, liver, and pancreas and accounts for ϳ10% of all cases of endstage renal disease. Mutation in either the polycystic kidney disease (PKD)1 or PKD2 gene accounts for 95% of all ADPKD cases. PKD1 encodes polycystin (PC)-1, a 4302-amino acid protein with a large extracellular domain, a G protein-coupled receptor proteolytic site (GPS), 11 predicted transmembrane (TM) domains, and an intracellular C terminus. The polycystin/lipoxygenase/␣-toxin (PLAT) domain is located in the first cytoplasmic loop between TM1 and TM2 and has been postulated to be involved in membrane-protein or protein-protein interactions (Bateman and Sandford, 1999). This domain is conserved in all PC-1 family members and also found in a variety of membrane-or lipid-associated proteins. Polycystin-2 (PC-2, encoded by PKD2) shares homology with the transient receptor protein (TRP) channels and acts as a nonselective cation channel. Defects in PC-1 or PC-2 signaling may result in epithelial dedifferentiation and cyst formation. Several signaling pathways regulated by PC-1 and PC-2 have been identified using in vitro approaches, including G protein signaling, JAK/STAT cell cycle regulation, and mechanotransduction (Boletta and Germino, 2003), but the physiological relevance to normal and disease states remains unclear.The nematode C. elegans is a simple but powerful animal model for studying basic molecular mechanisms underlying human ADPKD. The C. elegans LOV-1 and PKD-2 proteins are homologues of human PC-1 and PC-2 (Barr and Sternberg, 1999;Barr et al., 2001). lov-1 (location of vulva) and pkd-2 act nonredundantly in the same genetic pathway and are requi...

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Section: Discussionmentioning

confidence: 99%

ATP-2 Interacts with the PLAT Domain of LOV-1 and Is Involved inCaenorhabditis elegansPolycystin Signaling

Barr

2005

MBoC

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“…Release of nucleotides from renal cells was originally suggested from studies of cell lines [328,329,387]; it is now clear that native renal tubules are also able to secrete ATP. Nucleotide release from renal epithelia is both constitutive (suggestive of a 'purinergic tone') and activated by mechanical or agonistinduced stimuli.…”

Section: Release and Metabolism Of Nucleotidesmentioning

confidence: 99%

“…This leads to progressive dilation of tubules, which eventually become encapsulated in fluid-filled cysts that compress and destroy neighbouring tissue. ATP is released and reaches high concentrations within cysts [329,416]. Autosomal dominant polycystic disease (ADPKD) is characterised by bilateral cyst formation in the kidneys.…”

Section: Renal Injury and Failurementioning

confidence: 99%

Purinergic signalling in the kidney in health and disease

Burnstock

Evans

Bailey

2013

Purinergic Signalling

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The involvement of purinergic signalling in kidney physiology and pathophysiology is rapidly gaining recognition and this is a comprehensive review of early and recent publications in the field. Purinergic signalling involvement is described in several important intrarenal regulatory mechanisms, including tuboglomerular feedback, the autoregulatory response of the glomerular and extraglomerular microcirculation and the control of renin release. Furthermore, purinergic signalling influences water and electrolyte transport in all segments of the renal tubule. Reports about purine-and pyrimidine-mediated actions in diseases of the kidney, including polycystic kidney disease, nephritis, diabetes, hypertension and nephrotoxicant injury are covered and possible purinergic therapeutic strategies discussed.

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“…Here, it was proposed that PLC activation reduces the PIP 2 concentration in the inner face of the cell membrane and that membrane PIP 2 normally binds to the N-terminus of the β-ENaC subunit to increase the open probability of ENaC [35]. Accordingly, ENaC activity falls when P2Y 2 receptors are stimulated by extracellular UTP and when PIP 2 is scavenged by PLC to form soluble IP 3 and DAG. Unsurprisingly, P2Y 2 −/− gene deletion results in a facilitated Na + reabsorption in the kidney but, unexpectedly, it mainly involves a novel compensatory mechanism that increases the expression of Na-K-2Cl cotransporters in mouse thick ascending limb (TAL) epithelial cells, with only a marginal facilitation of ENaC activity and no significant change in ENaC number [36].…”

Section: Enac Modulation By P2rs In the Kidneymentioning

confidence: 99%

“…Extracellular ATP-based regulation of sodium excretion is not only found in the kidney but also occurs in other hollow organs where sodium ions can be reclaimed (lungs, gastrointestinal tract, pancreatic duct, hepatic and biliary ducts and eccrine sweat ducts). The pharmacological manipulation of P2R populations linked to ENaC may have therapeutic potential in helping to correct a number of disease states, such as cystic fibrosis [1,2], polycystic kidney disease [3] (and see article by Turner et al [4] in this Special Issue) and vascular hypertension associated with salt-retention [5][6][7]. Here, we review this new body of work on P2R/ENaC interactions in renal epithelia and address the role of ATP regulatory mechanisms in controlling the sodium balance in the extracellular fluid.…”

Section: Introductionmentioning

confidence: 99%

ENaC, renal sodium excretion and extracellular ATP

Wildman

Kang

King

2009

Purinergic Signalling

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Sodium balance determines the extracellular fluid volume and sets arterial blood pressure (BP). Chronically raised BP (hypertension) represents a major health risk in Western societies. The relationship between BP and renal sodium excretion (the pressure/natriuresis relationship) represents the key element in defining the BP homeostatic set point. The renin-angiotensin-aldosterone system (RAAS) makes major adjustments to the rates of renal sodium secretion, but this system works slowly over a period of hours to days. More rapid adjustments can be made by the sympathetic nervous system, although the kidney can function well without sympathetic nerves. Attention has now focussed on regulatory mechanisms within the kidney, including extracellular nucleotides and the P2 receptor system. Here, we discuss how extracellular ATP can control renal sodium excretion by altering the activity of epithelial sodium channels (ENaC) present in the apical membrane of principal cells. There remains considerable controversy over the molecular targets for released ATP, although the P2Y 2 receptor has received much attention. We review the available data and reflect on our own findings in which ATP-activated P2Y and P2X receptors make adjustments to ENaC activity and therefore sodium excretion.

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Autocrine extracellular purinergic signaling in epithelial cells derived from polycystic kidneys

Cited by 117 publications

References 52 publications

ATP-2 Interacts with the PLAT Domain of LOV-1 and Is Involved inCaenorhabditis elegansPolycystin Signaling

ATP-2 Interacts with the PLAT Domain of LOV-1 and Is Involved inCaenorhabditis elegansPolycystin Signaling

Purinergic signalling in the kidney in health and disease

ENaC, renal sodium excretion and extracellular ATP

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