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CD39-adenosinergic axis in renal pathophysiology and therapeutics

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Abstract

Extracellular ATP interacts with purinergic type 2 (P2) receptors and elicits many crucial biological functions. Extracellular ATP is sequentially hydrolyzed to ADP and AMP by the actions of defined nucleotidases, such as CD39, and AMP is converted to adenosine, largely by CD73, an ecto-5′-nucleotidase. Extracellular adenosine interacts with P1 receptors and often opposes the effects of P2 receptor activation. The balance between extracellular ATP and adenosine in the blood and extracellular fluid is regulated chiefly by the activities of CD39 and CD73, which constitute the CD39-adenosinergic axis. In recent years, several studies have shown this axis to play critical roles in transport of water/sodium, tubuloglomerular feedback, renin secretion, ischemia reperfusion injury, renal fibrosis, hypertension, diabetic nephropathy, transplantation, inflammation, and macrophage transformation. Important developments include global and targeted gene knockout and/or transgenic mouse models of CD39 or CD73, biological or small molecule inhibitors, and soluble engineered ectonucleotidases to directly impact the CD39-adenosinergic axis. This review presents a comprehensive picture of the multiple roles of CD39-adenosinergic axis in renal physiology, pathophysiology, and therapeutics. Scientific advances and greater understanding of the role of this axis in the kidney, in both health and illness, will direct development of innovative therapies for renal diseases.

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Acknowledgements

Authors’ work cited in this review has been supported by grants from the US Department of Veterans Affairs (I01BX000596); US Department of Defense Peer Reviewed Medical Research Program (W81XWH-16-1-0464); the National Institutes of Health (R21 DK-081041, P01-HL107152, R21 CA-164970); the National Kidney Foundation of Utah and Idaho, and the resources and facilities at the Veterans Affairs Salt Lake City Health Care System (Salt Lake City, UT).

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Authors and Affiliations

  1. Departments of Internal Medicine and Nutrition & Integrative Physiology, and Center on Aging, University of Utah Health, Salt Lake City, UT, USA

    Bellamkonda K. Kishore

  2. Nephrology Research, VA Salt Lake City Health Care System, 500 Foothill Drive (151M), Salt Lake City, UT, 84148, USA

    Bellamkonda K. Kishore

  3. Division of Gastroenterology/Hepatology and Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA

    Simon C. Robson

  4. School of Medicine, Faculty of Health, Deakin University, Geelong, VIC, 3220, Australia

    Karen M. Dwyer

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Correspondence to Bellamkonda K. Kishore.

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BKK received research funding from AstraZeneca, AB; SCR has research funding from Tizona and Boston Biomedical.

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Bellamkonda K. Kishore declares that he has no conflict of interest.

Simon C. Robson declares that he has no conflict of interest.

Karen M. Dwyer declares that she has no conflict of interest.

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Kishore, B.K., Robson, S.C. & Dwyer, K.M. CD39-adenosinergic axis in renal pathophysiology and therapeutics. Purinergic Signalling 14, 109–120 (2018). https://doi.org/10.1007/s11302-017-9596-x

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