Aquaporin (AQP) water channels are believed to have a key role in the urinary concentrating mechanism and the pathophysiology of nephrogenic diabetes insipidus (NDI). The kidney expresses at least 4 AQPs: AQP1 in proximal tubule, TDLH, and vasa recta; AQP2 in the apical membrane of principal cells in the collecting duct; and AQP3 and AQP4 in the basolateral membrane of the same cells.
Specific Aim 1 will define the role of AQPs in the urinary concentrating mechanism using transgenic knockout mice. Our lab developed the first transgenic mouse models to study water channel function-AQP1 and AQP4 knockout mice. These and AQP3 null mice will be used to define quantitatively the role of AQPs in renal water clearance. Renal function will be evaluated by urine/serum chemistries, isolated tubule and vasa recta microperfusion, and micropuncture.
Specific Aim 2 will characterize the cellular defect in hereditary NDI and test a novel therapeutic strategy. Preliminary data indicate that AQP2 mutations cause NDI by heterogeneous mechanisms involving defective AQP2 water channel function, accelerated degradation, and defective intracellular processing with ER retention. Transfected cells expressing NDI-causing AQP2 mutants will be used to characterize AQP2 misfolding, degradation mechanisms, and interactions with molecular chaperones. A mouse model of NDI will be developed and used to evaluate the efficacy of chemical chaperones to correct defective AQP2 function in NDI.
Specific Aim 3 will utilize novel biophysical methods to analyze specific aspects of AQP structure and function. Green fluorescent protein (GFP)-AQP chimeras will be used to define AQP mobility and association state in membranes and the cell biology of AQP2 trafficking. Methods will include fluorescence photobleaching recovery, energy transfer, and ratio imaging. Also, specific water/solute transporting properties (Pd, s s) of mammalian AQPs will be measured.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK035124-17
Application #
6634904
Study Section
General Medicine B Study Section (GMB)
Program Officer
Ketchum, Christian J
Project Start
1986-01-01
Project End
2004-05-31
Budget Start
2003-04-01
Budget End
2004-05-31
Support Year
17
Fiscal Year
2003
Total Cost
$396,707
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Smith, Alex J; Verkman, Alan S (2018) The ""glymphatic"" mechanism for solute clearance in Alzheimer's disease: game changer or unproven speculation? FASEB J 32:543-551
Tradtrantip, Lukmanee; Felix, Christian M; Spirig, Rolf et al. (2018) Recombinant IgG1 Fc hexamers block cytotoxicity and pathological changes in experimental in vitro and rat models of neuromyelitis optica. Neuropharmacology 133:345-353
Agbani, Ejaife O; Williams, Christopher M; Li, Yong et al. (2018) Aquaporin-1 regulates platelet procoagulant membrane dynamics and in vivo thrombosis. JCI Insight 3:
Tradtrantip, Lukmanee; Yao, Xiaoming; Su, Tao et al. (2017) Bystander mechanism for complement-initiated early oligodendrocyte injury in neuromyelitis optica. Acta Neuropathol 134:35-44
Tradtrantip, Lukmanee; Jin, Bjung-Ju; Yao, Xiaoming et al. (2017) Aquaporin-Targeted Therapeutics: State-of-the-Field. Adv Exp Med Biol 969:239-250
Cil, Onur; Phuan, Puay-Wah; Son, Jung-Ho et al. (2017) Phenylquinoxalinone CFTR activator as potential prosecretory therapy for constipation. Transl Res 182:14-26.e4
Jin, Byung-Ju; Verkman, A S (2017) Microfluidic platform for rapid measurement of transepithelial water transport. Lab Chip 17:887-895
Felix, Christian M; Lee, Sujin; Levin, Marc H et al. (2017) Pro-Secretory Activity and Pharmacology in Rabbits of an Aminophenyl-1,3,5-Triazine CFTR Activator for Dry Eye Disorders. Invest Ophthalmol Vis Sci 58:4506-4513
Yao, Xiaoming; Verkman, Alan S (2017) Complement regulator CD59 prevents peripheral organ injury in rats made seropositive for neuromyelitis optica immunoglobulin G. Acta Neuropathol Commun 5:57
Verkman, Alan S; Smith, Alex J; Phuan, Puay-Wah et al. (2017) The aquaporin-4 water channel as a potential drug target in neurological disorders. Expert Opin Ther Targets 21:1161-1170

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