P2Y2R and Cyst Growth in Polycystic Kidney Disease

Andre Kraus; Kathrin Skoczynski; Martin Brötsch; Nicolai Burzlaff; Jens Leipziger; Mario Schiffer; Maike Büttner-Herold; Bjoern Buchholz

doi:10.1681/ASN.0000000000000416

P2Y2R and Cyst Growth in Polycystic Kidney Disease

Andre Kraus, Kathrin Skoczynski, Martin Brötsch, Nicolai Burzlaff, Jens Leipziger, Mario Schiffer, Maike Büttner-Herold, Bjoern Buchholz

Department of Biomedicine - Forskning og uddannelse, Skou-bygningen

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Background Polycystic kidney disease (PKD) is characterized by continuous cyst growth, which results in a decline in kidney function.Deletion of P2Y2R and pharmacological antagonism of purinergic signaling significantly reduced cyst growth in an orthologous PKD mouse model.P2Y2R was expressed in cysts of human PKD nephrectomies, which makes P2Y2R a reasonable target for treatment of PKD.BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is characterized by multiple bilateral kidney cysts that gradually enlarge, resulting in a decline in kidney function. Cyst growth is significantly driven by ATP-dependent chloride secretion mediated by the ion channel TMEM16A. This pathway is further augmented in advanced stages of the disease by hypoxia and activation of hypoxia-inducible factor (HIF)-1α. The mechanisms by which ATP leads to activation of TMEM16A and how HIF-1α contributes to cyst growth in vivo have remained elusive.MethodsMice with an inducible tubule-specific deletion of Pkd1 were compared with mice with an additional codeletion of the purinergic receptor P2y2r. Furthermore, animals were challenged by pharmacological activation of HIF-1α and Pkd1-deficient mice were treated with suramin, an antagonist of purinergic signaling. In addition, expression of P2Y2R, TMEM16A, and HIF-1α was analyzed in nephrectomy samples from 27 patients with ADPKD.ResultsGenetic deletion of P2y2r significantly inhibited cyst growth in vivo. In addition, aggravation of the polycystic phenotype mediated by pharmacological activation of HIF-1α was reduced by deletion of P2y2r. Application of suramin to pharmacologically inhibit purinergic signaling also suppressed cyst enlargement in vivo. Analysis of kidney samples from 27 patients with ADPKD revealed significant expression of P2Y2R at the luminal site of the cyst-lining epithelium.ConclusionsP2Y2R was significantly expressed in human and mouse polycystic kidneys. Deletion and antagonism of P2Y2R reduced cyst enlargement in an ADPKD mouse model.

Original language	English
Journal	Journal of the American Society of Nephrology : JASN
Volume	35
Issue	10
Pages (from-to)	1351-1365
Number of pages	15
ISSN	1046-6673
DOIs	https://doi.org/10.1681/ASN.0000000000000416
Publication status	Published - 1 Oct 2024

Keywords

ADPKD
genetic renal disease
hypoxia
ion transport

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10.1681/ASN.0000000000000416

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@article{d976f0e797dc4badbc056afb9fbb01d7,

title = "P2Y2R and Cyst Growth in Polycystic Kidney Disease",

abstract = "Background Polycystic kidney disease (PKD) is characterized by continuous cyst growth, which results in a decline in kidney function.Deletion of P2Y2R and pharmacological antagonism of purinergic signaling significantly reduced cyst growth in an orthologous PKD mouse model.P2Y2R was expressed in cysts of human PKD nephrectomies, which makes P2Y2R a reasonable target for treatment of PKD.BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is characterized by multiple bilateral kidney cysts that gradually enlarge, resulting in a decline in kidney function. Cyst growth is significantly driven by ATP-dependent chloride secretion mediated by the ion channel TMEM16A. This pathway is further augmented in advanced stages of the disease by hypoxia and activation of hypoxia-inducible factor (HIF)-1α. The mechanisms by which ATP leads to activation of TMEM16A and how HIF-1α contributes to cyst growth in vivo have remained elusive.MethodsMice with an inducible tubule-specific deletion of Pkd1 were compared with mice with an additional codeletion of the purinergic receptor P2y2r. Furthermore, animals were challenged by pharmacological activation of HIF-1α and Pkd1-deficient mice were treated with suramin, an antagonist of purinergic signaling. In addition, expression of P2Y2R, TMEM16A, and HIF-1α was analyzed in nephrectomy samples from 27 patients with ADPKD.ResultsGenetic deletion of P2y2r significantly inhibited cyst growth in vivo. In addition, aggravation of the polycystic phenotype mediated by pharmacological activation of HIF-1α was reduced by deletion of P2y2r. Application of suramin to pharmacologically inhibit purinergic signaling also suppressed cyst enlargement in vivo. Analysis of kidney samples from 27 patients with ADPKD revealed significant expression of P2Y2R at the luminal site of the cyst-lining epithelium.ConclusionsP2Y2R was significantly expressed in human and mouse polycystic kidneys. Deletion and antagonism of P2Y2R reduced cyst enlargement in an ADPKD mouse model.",

keywords = "ADPKD, genetic renal disease, hypoxia, ion transport",

author = "Andre Kraus and Kathrin Skoczynski and Martin Br{\"o}tsch and Nicolai Burzlaff and Jens Leipziger and Mario Schiffer and Maike B{\"u}ttner-Herold and Bjoern Buchholz",

year = "2024",

month = oct,

day = "1",

doi = "10.1681/ASN.0000000000000416",

language = "English",

volume = "35",

pages = "1351--1365",

journal = "Journal of the American Society of Nephrology : JASN",

issn = "1046-6673",

publisher = "Wolters Kluwer Health",

number = "10",

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T1 - P2Y2R and Cyst Growth in Polycystic Kidney Disease

AU - Kraus, Andre

AU - Skoczynski, Kathrin

AU - Brötsch, Martin

AU - Burzlaff, Nicolai

AU - Leipziger, Jens

AU - Schiffer, Mario

AU - Büttner-Herold, Maike

AU - Buchholz, Bjoern

PY - 2024/10/1

Y1 - 2024/10/1

N2 - Background Polycystic kidney disease (PKD) is characterized by continuous cyst growth, which results in a decline in kidney function.Deletion of P2Y2R and pharmacological antagonism of purinergic signaling significantly reduced cyst growth in an orthologous PKD mouse model.P2Y2R was expressed in cysts of human PKD nephrectomies, which makes P2Y2R a reasonable target for treatment of PKD.BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is characterized by multiple bilateral kidney cysts that gradually enlarge, resulting in a decline in kidney function. Cyst growth is significantly driven by ATP-dependent chloride secretion mediated by the ion channel TMEM16A. This pathway is further augmented in advanced stages of the disease by hypoxia and activation of hypoxia-inducible factor (HIF)-1α. The mechanisms by which ATP leads to activation of TMEM16A and how HIF-1α contributes to cyst growth in vivo have remained elusive.MethodsMice with an inducible tubule-specific deletion of Pkd1 were compared with mice with an additional codeletion of the purinergic receptor P2y2r. Furthermore, animals were challenged by pharmacological activation of HIF-1α and Pkd1-deficient mice were treated with suramin, an antagonist of purinergic signaling. In addition, expression of P2Y2R, TMEM16A, and HIF-1α was analyzed in nephrectomy samples from 27 patients with ADPKD.ResultsGenetic deletion of P2y2r significantly inhibited cyst growth in vivo. In addition, aggravation of the polycystic phenotype mediated by pharmacological activation of HIF-1α was reduced by deletion of P2y2r. Application of suramin to pharmacologically inhibit purinergic signaling also suppressed cyst enlargement in vivo. Analysis of kidney samples from 27 patients with ADPKD revealed significant expression of P2Y2R at the luminal site of the cyst-lining epithelium.ConclusionsP2Y2R was significantly expressed in human and mouse polycystic kidneys. Deletion and antagonism of P2Y2R reduced cyst enlargement in an ADPKD mouse model.

AB - Background Polycystic kidney disease (PKD) is characterized by continuous cyst growth, which results in a decline in kidney function.Deletion of P2Y2R and pharmacological antagonism of purinergic signaling significantly reduced cyst growth in an orthologous PKD mouse model.P2Y2R was expressed in cysts of human PKD nephrectomies, which makes P2Y2R a reasonable target for treatment of PKD.BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is characterized by multiple bilateral kidney cysts that gradually enlarge, resulting in a decline in kidney function. Cyst growth is significantly driven by ATP-dependent chloride secretion mediated by the ion channel TMEM16A. This pathway is further augmented in advanced stages of the disease by hypoxia and activation of hypoxia-inducible factor (HIF)-1α. The mechanisms by which ATP leads to activation of TMEM16A and how HIF-1α contributes to cyst growth in vivo have remained elusive.MethodsMice with an inducible tubule-specific deletion of Pkd1 were compared with mice with an additional codeletion of the purinergic receptor P2y2r. Furthermore, animals were challenged by pharmacological activation of HIF-1α and Pkd1-deficient mice were treated with suramin, an antagonist of purinergic signaling. In addition, expression of P2Y2R, TMEM16A, and HIF-1α was analyzed in nephrectomy samples from 27 patients with ADPKD.ResultsGenetic deletion of P2y2r significantly inhibited cyst growth in vivo. In addition, aggravation of the polycystic phenotype mediated by pharmacological activation of HIF-1α was reduced by deletion of P2y2r. Application of suramin to pharmacologically inhibit purinergic signaling also suppressed cyst enlargement in vivo. Analysis of kidney samples from 27 patients with ADPKD revealed significant expression of P2Y2R at the luminal site of the cyst-lining epithelium.ConclusionsP2Y2R was significantly expressed in human and mouse polycystic kidneys. Deletion and antagonism of P2Y2R reduced cyst enlargement in an ADPKD mouse model.

KW - ADPKD

KW - genetic renal disease

KW - hypoxia

KW - ion transport

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U2 - 10.1681/ASN.0000000000000416

DO - 10.1681/ASN.0000000000000416

M3 - Journal article

C2 - 38848134

AN - SCOPUS:85205525122

SN - 1046-6673

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EP - 1365

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

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ER -

P2Y2R and Cyst Growth in Polycystic Kidney Disease

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