title: Acetazolamide Attenuates Lithium-Induced Nephrogenic Diabetes Insipidus.
abstract: To reduce lithium-induced nephrogenic diabetes insipidus (lithium-NDI), patients with bipolar disorder are treated with thiazide and amiloride, which are thought to induce antidiuresis by a compensatory increase in prourine uptake in proximal tubules. However, thiazides induced antidiuresis and alkalinized the urine in lithium-NDI mice lacking the sodium-chloride cotransporter, suggesting that inhibition of carbonic anhydrases (CAs) confers the beneficial thiazide effect. Therefore, we tested the effect of the CA-specific blocker acetazolamide in lithium-NDI. In collecting duct (mpkCCD) cells, acetazolamide reduced the cellular lithium content and attenuated lithium-induced downregulation of aquaporin-2 through a mechanism different from that of amiloride. Treatment of lithium-NDI mice with acetazolamide or thiazide/amiloride induced similar antidiuresis and increased urine osmolality and aquaporin-2 abundance. Thiazide/amiloride-treated mice showed hyponatremia, hyperkalemia, hypercalcemia, metabolic acidosis, and increased serum lithium concentrations, adverse effects previously observed in patients but not in acetazolamide-treated mice in this study. Furthermore, acetazolamide treatment reduced inulin clearance and cortical expression of sodium/hydrogen exchanger 3 and attenuated the increased expression of urinary PGE2 observed in lithium-NDI mice. These results show that the antidiuresis with acetazolamide was partially caused by a tubular-glomerular feedback response and reduced GFR. The tubular-glomerular feedback response and/or direct effect on collecting duct principal or intercalated cells may underlie the reduced urinary PGE2 levels with acetazolamide, thereby contributing to the attenuation of lithium-NDI. In conclusion, CA activity contributes to lithium-NDI development, and acetazolamide attenuates lithium-NDI development in mice similar to thiazide/amiloride but with fewer adverse effects.
authors.affiliation: Departments of Physiology and.
authors.forename: Theun
authors.initials: T
authors.lastname: de Groot
authors.affiliation: Departments of Physiology and.
authors.forename: Anne P
authors.initials: AP
authors.lastname: Sinke
authors.affiliation: Departments of Physiology and.
authors.forename: Marleen L A
authors.initials: ML
authors.lastname: Kortenoeven
authors.affiliation: Departments of Physiology and.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Alsady
authors.affiliation: Vivium Care Group, Huizen, The Netherlands;
authors.forename: Ruben
authors.initials: R
authors.lastname: Baumgarten
authors.affiliation: Institute of Physiology, Zurich Centre for Integrative Human Physiology, Zurich, Switzerland; and.
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.affiliation: Anatomy, University of Zurich, Zurich, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Loffing
authors.affiliation: Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands;
authors.forename: Jack F
authors.initials: JF
authors.lastname: Wetzels
authors.affiliation: Departments of Physiology and peter.deen@Radboudumc.nl.
authors.forename: Peter M T
authors.initials: PM
authors.lastname: Deen
mesh_terms: D000086:Acetazolamide / Q000627:therapeutic use*; D000584:Amiloride / Q000627:therapeutic use; D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D018500:Diabetes Insipidus, Nephrogenic / Q000139:chemically induced* / Q000188:drug therapy*; D004232:Diuretics / Q000627:therapeutic use*; D005260:Female; D018020:Lithium Compounds / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D049993:Sodium Chloride Symporter Inhibitors / Q000627:therapeutic use
chemical_list: D051399:Aquaporin 2; D004232:Diuretics; D018020:Lithium Compounds; D049993:Sodium Chloride Symporter Inhibitors; D000584:Amiloride; D000086:Acetazolamide
keywords: cell and transport physiology; diabetes insipidus; diuretics; osmolality; pathophysiology of renal disease and progression; water transport