title: PPARγ agonist-induced fluid retention depends on αENaC expression in connecting tubules.
abstract: OBJECTIVE
  Thiazolidinediones (TZDs, like rosiglitazone (RGZ)) are peroxisome proliferator-activated receptor γ (PPARγ) agonists used to treat type 2 diabetes. Clinical limitations include TZD-induced fluid retention and body weight (BW) increase, which are inhibited by amiloride, an epithelial-sodium channel (ENaC) blocker. RGZ-induced fluid retention is maintained in mice with αENaC knockdown in the collecting duct (CD). Since ENaC in the connecting tubule (CNT) rather than in CD appears to be critical for normal NaCl retention, we aimed to further explore the role of ENaC in CNT in RGZ-induced fluid retention.
  
  
  METHODS
  Mice with conditional inactivation of αENaC in both CNT and CD were used (αENaC lox/lox AQP2-Cre; 'αENaC-CNT/CD-KO') and compared with littermate controls (αENaC lox/lox mice; 'WT'). BW was monitored and total body water (TBW) and extracellular fluid volume (ECF) were determined by bioelectrical impedance spectroscopy (BIS) before and after RGZ (320 mg/kg diet for 10 days).
  
  
  RESULTS
  On regular NaCl diet, αENaC-CNT/CD-KO had normal BW, TBW, ECF, hematocrit, and plasma Na(+), K(+), and creatinine, associated with an increase in plasma aldosterone compared with WT. Challenging αENaC-CNT/CD-KO with a low NaCl diet unmasked impaired NaCl and K homeostasis, consistent with effective knockdown of αENaC. In WT, RGZ increased BW (+6.1%), TBW (+8.4%) and ECF (+10%), consistent with fluid retention. These changes were significantly attenuated in αENaC-CNT/CD-KO (+3.4, 1.3, and 4.3%).
  
  
  CONCLUSIONS
  Together with the previous studies, the current results are consistent with a role of αENaC in CNT in RGZ-induced fluid retention, which dovetails with the physiological relevance of ENaC in this segment.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Fu
authors.forename: Maria
authors.initials: M
authors.lastname: Gerasimova
authors.forename: Falk
authors.initials: F
authors.lastname: Batz
authors.forename: Alexander
authors.initials: A
authors.lastname: Kuczkowski
authors.forename: Yasaman
authors.initials: Y
authors.lastname: Alam
authors.forename: Paul W
authors.initials: PW
authors.lastname: Sanders
authors.forename: Caroline
authors.initials: C
authors.lastname: Ronzaud
authors.forename: Edith
authors.initials: E
authors.lastname: Hummler
authors.forename: Volker
authors.initials: V
authors.lastname: Vallon
mesh_terms: D000818:Animals; D001826:Body Fluids / Q000187:drug effects / Q000378:metabolism; D004039:Diet, Sodium-Restricted; D004487:Edema / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects; D007685:Kidney Tubules, Collecting / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000819:agonists*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000009:adverse effects*; D015430:Weight Gain / Q000187:drug effects
chemical_list: D053503:Epithelial Sodium Channels; D007004:Hypoglycemic Agents; D047495:PPAR gamma; C507047:Scnn1a protein, mouse; D045162:Thiazolidinediones; D000077154:Rosiglitazone