Nephrogenic diabetes insipidus (NDI) due to lithium therapy for bipolar disorder is one of the major nephrological problems among Veterans. NDI is a debilitating condition with an elevated risk of morbidity and even mortality, especially in elderly Veterans. Currently used therapeutic modalities for NDI are encountered with varying degrees of success as well as side effects, including lithium intoxication. Refinement and/or replacement of the current side effect-prone therapies with new drugs based on an improved understanding of molecular pathophysiology of lithium-induced NDI should result in improved efficacy and fewer side effects. Research carried out by us during the current funding period provided significant insights into the potential role of purinergic signaling in the genesis of lithium-induced NDI. These are: (i) purinergic signaling may play a potential overarching role in balancing the effect of arginine vasopressin (AVP) on the urinary concentration mechanism; (ii) in lithium-induced NDI, purinergic signaling in the medullary collecting duct is sensitized and involves more than one subtype of P2Y receptors; and (iii) P2Y2 receptor gene knockout mice are significantly resistant to the development of lithium-induced NDI, suggesting the potential role of purinergic signaling in the genesis of lithium-induced NDI. Based on our novel and significant observations we hypothesize that a deeper understanding of the role of renal purinergic signaling in Li-induced NDI offers better therapeutic modalities. A new class of drugs that target purinergic signaling may improve the safety and/or efficacy of the current medications in combination therapies, or replace them in the treatment of Li-induced NDI. The specific objective of the project are: 1) to investigate the role of purinergic signaling in the development of Li-induced AVP resistance using P2Y2 receptor knockout and wild type mice; 2) to investigate the role of purinergic signaling in Li-induced AVP resistance of medullary collecting duct using primary cultures of mouse inner medullary collecting duct cells; and 3) to investigate the effect of amiloride and COX-2 inhibition on Li-induced NDI in a background of blunted purinergic signaling. To achieve our objectives we will use P2Y2 receptor knockout mice, rats and cell culture models, and employ molecular, functional, immunohistochemical and cell signaling techniques.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000596-02
Application #
8195888
Study Section
Nephrology (NEPH)
Project Start
2010-04-01
Project End
2014-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
2
Fiscal Year
2011
Total Cost
Indirect Cost
Name
VA Salt Lake City Healthcare System
Department
Type
DUNS #
009094756
City
Salt Lake City
State
UT
Country
United States
Zip Code
84148
Peti-Peterdi, János; Kishore, Bellamkonda K; Pluznick, Jennifer L (2016) Regulation of Vascular and Renal Function by Metabolite Receptors. Annu Rev Physiol 78:391-414
Zhang, Yue; Peti-Peterdi, János; Heiney, Kristina M et al. (2015) Clopidogrel attenuates lithium-induced alterations in renal water and sodium channels/transporters in mice. Purinergic Signal 11:507-18
Kishore, B K; Carlson, N G; Ecelbarger, C M et al. (2015) Targeting renal purinergic signalling for the treatment of lithium-induced nephrogenic diabetes insipidus. Acta Physiol (Oxf) 214:176-88
Thimm, D; Schiedel, A C; Peti-Peterdi, J et al. (2015) The nucleobase adenine as a signalling molecule in the kidney. Acta Physiol (Oxf) 213:808-18
Zhang, Yue; Robson, Simon C; Morris, Kaiya L et al. (2015) Impaired natriuretic response to high-NaCl diet plus aldosterone infusion in mice overexpressing human CD39, an ectonucleotidase (NTPDase1). Am J Physiol Renal Physiol 308:F1398-408
Zhang, Yue; Peti-Peterdi, Janos; Müller, Christa E et al. (2015) P2Y12 Receptor Localizes in the Renal Collecting Duct and Its Blockade Augments Arginine Vasopressin Action and Alleviates Nephrogenic Diabetes Insipidus. J Am Soc Nephrol 26:2978-87