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Pannexin-1/P2X7 interaction promotes excessive ATP release in kidney cysts and ADPKD progression via reduced NaCl reabsorption

Award Number: R01DK123266
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY ADPKD (autosomal dominant polycystic kidney disease) is the most prevalent inherited progressive kidney disease affecting 1:1000 live births in USA. Genetic predisposition is necessary for polycystic kidney disease (PKD) initiation, although other, incompletely identified downstream processes are required for cyst growth. Their characterization may provide a unique opportunity for clinical interventions. One of the poorly studied phenomena in PKD is high adenosine-3-phosphate (ATP) content in cysts. As a powerful regulator of epithelial water-electrolyte transport, ATP can decrease reabsorption in the collecting duct system where ~70% of ADPKD cysts develop. Particularly, as a paracrine agent, ATP limits activity of the epithelial sodium channel (ENaC). Reduced ENaC activity is recognized as pivotal factors of cytogenesis. However, the mechanism of the pathogenic ATP release and its role in Na+ transport during cyst development remains unclear. Pannexins are transmembrane proteins which were recently characterized to be capable of ATP release. Interaction with P2X7 receptors promotes activation of pannexin-1 (PANX1) by forming high-conductive channels serving as ATP-permeable pores. Our recently published and pilot data indicate that PKD cysts exhibit a unique pathogenic situation when abnormally high level of both PANX1 and P2X7 express in cyst-lining cells. We hypothesize that the P2X7-dependent switching of pannexin-1 to the active form is the central mechanism of ATP accumulation in the cysts and their growth. Our data suggest that luminal expression of both PANX1 and P2X7 proteins dramatically increase in the human ADPKD cysts and in rodent models of PKD. Moreover, pharmacological and genetic targeting of PANX1 channels and P2X7 receptors slows cyst growth. In the proposed project we plan to study if PANX1/P2X7 interaction contributes to ATP release in the hypomorphic Pkd1RC/RC mouse model of ADPKD and how this mechanism reduces reabsorption across the cystic epithelium. We will investigate Panx1 and P2rx7 expression during development of ADPKD. A set of experiments involving patch-clamp is designed in cell cultures and native cysts to study regulation of PANX1-mediated ATP release. As purinergic signaling is important for epithelial transport we will characterize calcium signaling and ENaC function in freshly isolated cysts and normal collecting ducts. Breeding of Panx1 mutanat mice with Pkd1RC/RC strain tests if genetic ablation of pannexin-1 inhibits cystogenesis by limiting ATP release and improving sodium reabsorption. We also plan to study the potential of repurposing probenecid, a known gout remedy and pannexin-1 blocker, for ADPKD treatment.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $398,761 )
2023	2023	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/30/2023	NON-COMPETING CONTINUATION	$398,761
														Subtotal = $398,761

Issue Date FY: 2022 ( Subtotal = $400,209 )
2022	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/27/2022	NON-COMPETING CONTINUATION	$400,209
														Subtotal = $400,209

Issue Date FY: 2021 ( Subtotal = $400,209 )
2021	2021	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/1/2021	NEW	$400,209
														Subtotal = $400,209

Grand Total All Awards = $1,199,179

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Pannexin-1/P2X7 interaction promotes excessive ATP release in kidney cysts and ADPKD progression via reduced NaCl reabsorption

Award Number: R01DK123266

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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