title: Urine concentration in the diabetic mouse requires both urea and water transporters.
abstract: The regulation of the inner medullary collecting duct (IMCD) urea transporters (UT-A1, UT-A3) and aquaporin-2 (AQP2) and their interactions in diabetic animals is unknown. We investigated whether the urine concentrating defect in diabetic animals was a function of AQP2, the UT-As, or both transporters. UT-A1/UT-A3 knockout (UT-A1/A3 KO) mice produce dilute urine. We gave wild-type (WT) and UT-A1/A3 KO mice vasopressin via minipump for 7 days. In WT mice, vasopressin increased urine osmolality from 3,000 to 4,550 mosmol/kgH(2)O. In contrast, urine osmolality was low (800 mosmol/kgH(2)O) in the UT-A1/A3 KOs and remained low following vasopressin. Surprisingly, AQP2 protein abundance increased in UT-A1/A3 KO (114%) and WT (92%) mice. To define the role of UT-A1 and UT-A3 in the diabetic responses, WT and UT-A1/A3 KO mice were injected with streptozotocin (STZ). UT-A1/A3 KO mice showed only 40% survival at 7 days post-STZ injection compared with 70% in WT. AQP2 did not increase in the diabetic UT-A1/A3 KO mice compared with a 133% increase in WT diabetic mice. Biotinylation studies in rat IMCDs showed that membrane accumulation of UT-A1 increased by 68% in response to vasopressin in control rats but was unchanged by vasopressin in diabetic rat IMCDs. We conclude that, even with increased AQP2, UT-A1/UT-A3 is essential to optimal urine concentration. Furthermore, UT-A1 may be maximally membrane associated in diabetic rat inner medulla, making additional stimulation by vasopressin ineffective.
authors.affiliation: Emory Univ. Renal Division, Atlanta, GA 30322, USA. tilori@emory.edu
authors.forename: Titilayo O
authors.initials: TO
authors.lastname: Ilori
authors.forename: Mitsi A
authors.initials: MA
authors.lastname: Blount
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Martin
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Sands
authors.forename: Janet D
authors.initials: JD
authors.lastname: Klein
mesh_terms: D000818:Animals; D051399:Aquaporin 2 / Q000502:physiology*; D001127:Arginine Vasopressin / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology* / Q000652:urine; D007668:Kidney; D007671:Kidney Concentrating Ability / Q000187:drug effects / Q000502:physiology*; D007685:Kidney Tubules, Collecting / Q000502:physiology; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D009994:Osmolar Concentration; D051381:Rats; D000096982:Urea Transporters
chemical_list: D051399:Aquaporin 2; D001127:Arginine Vasopressin; D026901:Membrane Transport Proteins; D000096982:Urea Transporters; C496024:Aqp2 protein, mouse