title: Amiloride restores renal medullary osmolytes in lithium-induced nephrogenic diabetes insipidus.
abstract: In lithium-induced nephrogenic diabetes insipidus (NDI), alterations in renal medullary osmolyte concentrations have been assumed but never investigated. Amiloride can modify lithium-induced NDI, but the impact of amiloride in lithium-induced NDI on renal medullary osmolytes, aquaporins, and urea transporters is unknown and is the basis of this study. Rats fed lithium (60 mmol/kg dry food) over 4 wk developed NDI. Urine osmolality fell to 287 +/- 19 mosmol/kgH(2)O (controls 1,211 +/- 90 mosmol/kgH(2)O). Organic osmolytes in the renal medulla showed significant decreases compared with controls [inositol 221 +/- 35 to 85 +/- 10 mmol/kg protein; sorbitol 35 +/- 9 to 3 +/- 1 mmol/kg protein; glycerophosphorylcholine (GPC) 352 +/- 80 to 91 +/- 20 mmol/kg protein; and glycine betaine 69 +/- 11 to 38 +/- 38 mmol/kg protein]. Medullary urea content fell from 2,868 +/- 624 to 480 +/- 117 mmol/kg protein. Concurrent administration of amiloride (0.2 mmol/l) in the drinking water restored urine osmolality (1,132 +/- 154 mosmol/kgH(2)O), and reduced urine volume. Medullary osmolyte content were restored to control values (inositol, 232 +/- 12; sorbitol 32 +/- 6; GPC, 244 +/- 26; glycine betaine, 84 +/- 5 mmol/kg protein). Medullary urea rose to 2,122 +/- 305 mmol/kg protein. Reduced AQP2, AQP3, and urea transporter (UT-A1) expression was significantly reversed following amiloride therapy. Data presented here provide further understanding of how amiloride may substantially restore the lithium-induced impaired renal concentrating mechanism.
authors.affiliation: Department of Physiology, University of Otago, Dunedin, New Zealand.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Bedford
authors.forename: John P
authors.initials: JP
authors.lastname: Leader
authors.forename: Rena
authors.initials: R
authors.lastname: Jing
authors.forename: Logan J
authors.initials: LJ
authors.lastname: Walker
authors.forename: Janet D
authors.initials: JD
authors.lastname: Klein
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Sands
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Walker
mesh_terms: D000584:Amiloride / Q000627:therapeutic use*; D000818:Animals; D051398:Aquaporin 1 / Q000235:genetics; D018500:Diabetes Insipidus, Nephrogenic / Q000139:chemically induced* / Q000188:drug therapy*; D004195:Disease Models, Animal; D007679:Kidney Medulla / Q000187:drug effects / Q000473:pathology*; D008094:Lithium / Q000378:metabolism; D016651:Lithium Carbonate / Q000633:toxicity*; D008297:Male; D011188:Potassium / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012964:Sodium / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D051398:Aquaporin 1; D016651:Lithium Carbonate; D000584:Amiloride; D008094:Lithium; D012964:Sodium; D011188:Potassium