Nephrogenic diabetes insipidus (NDI) is a disease characterized by the production of very large quantities of dilute urine from an inability of the kidney to respond to vasopressin. NDI can be either congenital or acquired. Congenital NDI results from mutations in the type 2 vasopressin receptor (V2R) in 90% of families (in which the mutation is known) and in AQP2 in the other 10%. The most common cause of acquired NDI is lithium treatment, a medication that interferes with cAMP signaling. In patients with V2R mutations or taking lithium, there are no mutations in either the AQP2 or UT-A1 proteins, suggesting that if it is possible to phosphorylate these proteins and increase their apical membrane accumulation independent of vasopressin or cAMP, then one may be able to treat, or at least lessen the severity of, the NDI. Therefore, we looked for a kinase that could phosphorylate both AQP2 and UT-A1 independent of vasopressin. Adenosine monophosphate kinase (AMPK) is an energy-sensing kinase that can be stimulated by osmotic stress and hypoxia. AMPK has never been studied in inner medulla, which is normally hypertonic and hypoxic. We have preliminary data showing that AMPK phosphorylates AQP2 and UT-A1, both in vitro and in native rat inner medullary collecting ducts. We also have preliminary data showing that metformin increases urine osmolality in mice lacking a V2R, a mouse model of congenital NDI. In this application, we will test the hypothesis that AMPK, independent of vasopressin, increases urine concentrating ability through increases in AQP2 and UT-A1 phosphorylation, apical plasma membrane accumulation, and function.
Specific Aim 1 will test whether AQP2 and UT-A1 are substrates for phosphorylation by AMPK.
Specific Aim 2 will test whether phosphorylation of AQP2 and UT-A1 by AMPK increases the apical membrane accumulation of these two proteins.
Specific Aim 3 will test whether activation of AMPK increases urea and water permeabilities, and urine concentrating ability in animal models of NDI. If our hypothesis is correct, then AMPK activators would be a novel therapeutic option for congenital NDI due to V2R mutations, and for acquired forms of NDI due to interference with cAMP.

Public Health Relevance

Nephrogenic diabetes insipidus (NDI) is a disease characterized by the production of very large quantities of dilute urine from an inability of the kidney to respond to vasopressin. Our preliminary data indicate that activation of adenosine monophosphate kinase (AMPK) is a non-vasopressin mechanism for increasing urea and water transport, which in turn increases urine concentrating ability. Our studies could form the basis for future translational studies of AMPK activators as a novel therapeutic approach to congenital NDI due to V2R mutations, and for acquired forms of NDI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK041707-19A1
Application #
8758204
Study Section
Special Emphasis Panel (KMBD)
Program Officer
Ketchum, Christian J
Project Start
1989-08-01
Project End
2018-03-31
Budget Start
2014-08-01
Budget End
2015-03-31
Support Year
19
Fiscal Year
2014
Total Cost
$339,300
Indirect Cost
$121,800
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Klein, Janet D; Sands, Jeff M (2016) Urea transport and clinical potential of urearetics. Curr Opin Nephrol Hypertens 25:444-51
Sands, Jeff M (2016) Water, Water Everywhere: A New Cause and a New Treatment for Nephrogenic Diabetes Insipidus. J Am Soc Nephrol 27:1872-4
Chen, Ling; LaRocque, Lauren M; Efe, Orhan et al. (2016) Effect of Dapagliflozin Treatment on Fluid and Electrolyte Balance in Diabetic Rats. Am J Med Sci 352:517-523
Ren, Huiwen; Yang, Baoxue; Ruiz, Joseph A et al. (2016) Phosphatase inhibition increases AQP2 accumulation in the rat IMCD apical plasma membrane. Am J Physiol Renal Physiol 311:F1189-F1197
Wang, Juan; Wang, Xiaonan H; Wang, Haidong et al. (2016) Urea Transporter B and MicroRNA-200c Differ in Kidney Outer Versus Inner Medulla Following Dehydration. Am J Med Sci 352:296-301
Reed, Galen D; von Morze, Cornelius; Verkman, Alan S et al. (2016) Imaging Renal Urea Handling in Rats at Millimeter Resolution using Hyperpolarized Magnetic Resonance Relaxometry. Tomography 2:125-135
Keller, Raymond W; Bailey, James L; Wang, Yanhua et al. (2016) Urea transporters and sweat response to uremia. Physiol Rep 4:
Klein, Janet D; Wang, Yanhua; Blount, Mitsi A et al. (2016) Metformin, an AMPK activator, stimulates the phosphorylation of aquaporin 2 and urea transporter A1 in inner medullary collecting ducts. Am J Physiol Renal Physiol 310:F1008-12
Sands, Jeff M; Klein, Janet D (2016) Physiological insights into novel therapies for nephrogenic diabetes insipidus. Am J Physiol Renal Physiol 311:F1149-F1152
Efe, Orhan; Klein, Janet D; LaRocque, Lauren M et al. (2016) Metformin improves urine concentration in rodents with nephrogenic diabetes insipidus. JCI Insight 1:

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