title: Increased susceptibility of db/db mice to rosiglitazone-induced plasma volume expansion: role of dysregulation of renal water transporters.
abstract: Thiazolidinediones (TZDs), which are synthetic peroxisome proliferator-activated receptor subtype-γ (PPARγ), agonists are highly effective for treatment of type 2 diabetes. However, the side effect of fluid retention has significantly limited their application. Most of the previous studies addressing TZD-induced fluid retention employed healthy animals. The underlying mechanism of this phenomenon is still incompletely understood, particularly in the setting of disease state. The present study was undertaken to examine rosiglitazone (RGZ)-induced fluid retention in db/db mice and to further investigate the underlying mechanism. In response to RGZ treatment, db/db mice exhibited an accelerated plasma volume expansion as assessed by hematocrit (Hct) and fluorescent nanoparticles, in parallel with a greater increase in body weight, compared with lean controls. In response to RGZ-induced fluid retention, urinary Na(+) excretion and urine volume were significantly increased in lean mice. In contrast, the natriuretic and diuretic responses were significantly blunted in db/db mice. RGZ db/db mice exhibited a parallel decrease in plasma Na(+) concentration and plasma osmolality, contrasting to unchanged levels in lean controls. Imunoblotting analysis showed downregulation of renal aquaporin (AQP) 2 expression in response to RGZ treatment in lean mice but not in db/db mice. Renal AQP3 protein expression was unaffected by RGZ treatment in lean mice but was elevated in db/db mice. In contrast, the expression of Na(+)/H(+) exchanger-3 (NHE3) and NKCC2 was unchanged in either mouse strain. Together these results suggest that compared with the lean controls, db/db mice exhibited accelerated plasma volume expansion that was in part due to the inappropriate response of renal water transporters.
authors.affiliation: Univ. of Utah and Veterans Affairs Medical Center, Division of Nephrology and Hypertension, 30N 1900E, RM 4C224, Salt Lake City, UT 84132. Tianxin.Yang@hsc.utah.edu B. Yang Peking University (e-mail: baoxue@bjmu.edu.cn.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Jia
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Yang
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kakizoe
authors.forename: Mi
authors.initials: M
authors.lastname: Liu
authors.forename: Shufeng
authors.initials: S
authors.lastname: Zhou
authors.forename: Ren
authors.initials: R
authors.lastname: Chen
authors.forename: Baoxue
authors.initials: B
authors.lastname: Yang
authors.forename: Tianxin
authors.initials: T
authors.lastname: Yang
mesh_terms: D000818:Animals; D051399:Aquaporin 2 / Q000187:drug effects / Q000378:metabolism; D051400:Aquaporin 3 / Q000187:drug effects / Q000378:metabolism; D001692:Biological Transport; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001834:Body Water / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy*; D004195:Disease Models, Animal; D004231:Diuresis / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D009318:Natriuresis / Q000187:drug effects; D009994:Osmolar Concentration; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D010953:Plasma Volume / Q000187:drug effects*; D000077154:Rosiglitazone; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1 / Q000378:metabolism; D045162:Thiazolidinediones / Q000633:toxicity*; D014280:Triglycerides / Q000097:blood; D014882:Water-Electrolyte Balance / Q000187:drug effects*; D014883:Water-Electrolyte Imbalance / Q000097:blood / Q000139:chemically induced*; D015430:Weight Gain / Q000187:drug effects
chemical_list: C496024:Aqp2 protein, mouse; C496028:Aqp3 protein, mouse; D051399:Aquaporin 2; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047495:PPAR gamma; C000613385:SLC9A3 protein, human; C578715:Slc12a1 protein, mouse; C000613386:Slc9a3 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D064466:Solute Carrier Family 12, Member 1; D045162:Thiazolidinediones; D014280:Triglycerides; D000077154:Rosiglitazone; D051400:Aquaporin 3
keywords: PPARγ; db/db; nanoparticle; plasma volume; rosiglitazone