title: Absence of PKC-alpha attenuates lithium-induced nephrogenic diabetes insipidus.
abstract: Lithium, an effective antipsychotic, induces nephrogenic diabetes insipidus (NDI) in ∼40% of patients. The decreased capacity to concentrate urine is likely due to lithium acutely disrupting the cAMP pathway and chronically reducing urea transporter (UT-A1) and water channel (AQP2) expression in the inner medulla. Targeting an alternative signaling pathway, such as PKC-mediated signaling, may be an effective method of treating lithium-induced polyuria. PKC-alpha null mice (PKCα KO) and strain-matched wild type (WT) controls were treated with lithium for 0, 3 or 5 days. WT mice had increased urine output and lowered urine osmolality after 3 and 5 days of treatment whereas PKCα KO mice had no change in urine output or concentration. Western blot analysis revealed that AQP2 expression in medullary tissues was lowered after 3 and 5 days in WT mice; however, AQP2 was unchanged in PKCα KO. Similar results were observed with UT-A1 expression. Animals were also treated with lithium for 6 weeks. Lithium-treated WT mice had 19-fold increased urine output whereas treated PKCα KO animals had a 4-fold increase in output. AQP2 and UT-A1 expression was lowered in 6 week lithium-treated WT animals whereas in treated PKCα KO mice, AQP2 was only reduced by 2-fold and UT-A1 expression was unaffected. Urinary sodium, potassium and calcium were elevated in lithium-fed WT but not in lithium-fed PKCα KO mice. Our data show that ablation of PKCα preserves AQP2 and UT-A1 protein expression and localization in lithium-induced NDI, and prevents the development of the severe polyuria associated with lithium therapy.
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Jae H
authors.initials: JH
authors.lastname: Sim
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Nathaniel J
authors.initials: NJ
authors.lastname: Himmel
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Sara K
authors.initials: SK
authors.lastname: Redd
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Fadi E
authors.initials: FE
authors.lastname: Pulous
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Rogers
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Lauren N
authors.initials: LN
authors.lastname: Black
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Seongun M
authors.initials: SM
authors.lastname: Hong
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Tobias N
authors.initials: TN
authors.lastname: von Bergen
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Mitsi A
authors.initials: MA
authors.lastname: Blount
mesh_terms: D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D018500:Diabetes Insipidus, Nephrogenic / Q000139:chemically induced / Q000201:enzymology*; D006706:Homeostasis; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008094:Lithium; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D018345:Mice, Knockout; D051571:Protein Kinase C-alpha / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport; D000096982:Urea Transporters
chemical_list: D051399:Aquaporin 2; D008094:Lithium; D026901:Membrane Transport Proteins; D051571:Protein Kinase C-alpha; D000096982:Urea Transporters; C496024:Aqp2 protein, mouse