title: 4-PBA improves lithium-induced nephrogenic diabetes insipidus by attenuating ER stress.
abstract: Endoplasmic reticulum (ER) stress has been implicated in some types of glomerular and tubular disorders. The objectives of this study were to elucidate the role of ER stress in lithium-induced nephrogenic diabetes insipidus (NDI) and to investigate whether attenuation of ER stress by 4-phenylbutyric acid (4-PBA) improves urinary concentrating defect in lithium-treated rats. Wistar rats received lithium (40 mmol/kg food), 4-PBA (320 mg/kg body wt by gavage every day), or no treatment (control) for 2 wk, and they were dehydrated for 24 h before euthanasia. Lithium treatment resulted in increased urine output and decreased urinary osmolality, which was significantly improved by 4-PBA. 4-PBA also prevented reduced protein expression of aquaporin-2 (AQP2), pS256-AQP2, and pS261-AQP2 in the inner medulla of kidneys from lithium-treated rats after 24-h dehydration. Lithium treatment resulted in increased expression of ER stress markers in the inner medulla, which was associated with dilated cisternae and expansion of ER in the inner medullary collecting duct (IMCD) principal cells. Confocal immunofluorescence studies showed colocalization of a molecular chaperone, binding IgG protein (BiP), with AQP2 in principal cells. Immunohistochemistry demonstrated increased intracellular expression of BiP and decreased AQP2 expression in IMCD principal cells of kidneys from lithium-treated rats. 4-PBA attenuated expression of ER stress markers and recovered ER morphology. In IMCD suspensions isolated from lithium-treated rats, 4-PBA incubation was also associated with increased AQP2 expression and ameliorated ER stress. In conclusion, in experimental lithium-induced NDI, 4-PBA improved the urinary concentrating defect and increased AQP2 expression, likely via attenuating ER stress in IMCD principal cells.
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Peili
authors.initials: P
authors.lastname: Zheng
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Renfei
authors.initials: R
authors.lastname: Luo
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Tiezheng
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Clinical Laboratory, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; and.
authors.forename: Pinning
authors.initials: P
authors.lastname: Feng
authors.affiliation: Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Xinling
authors.initials: X
authors.lastname: Liang
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Chunling
authors.initials: C
authors.lastname: Li
authors.affiliation: Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; wangwd6@mail.sysu.edu.cn.
authors.forename: Weidong
authors.initials: W
authors.lastname: Wang
mesh_terms: D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D002082:Butylamines / Q000494:pharmacology / Q000627:therapeutic use*; D018500:Diabetes Insipidus, Nephrogenic / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008094:Lithium; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome; D014554:Urination / Q000187:drug effects
chemical_list: C121358:4-phenylbutylamine; D051399:Aquaporin 2; D002082:Butylamines; D008094:Lithium
keywords: AQP2; BiP/GRP78; endoplasmic reticulum; lithium