Time course of AQP-2 and ENaC regulation in the kidney in response to PPAR agonists associated with marked edema in rats

Pharmacol Res. 2008 May;57(5):383-92. doi: 10.1016/j.phrs.2008.03.013. Epub 2008 Apr 7.

Abstract

Peroxisome-proliferator-activated receptor (PPAR-gamma) agonists improve insulin sensitivity, but are associated with edema. Increased distal tubule sodium and water reabsorption through the epithelial sodium channel (ENaC) and aquaporin-2 (AQP-2) have been suggested to play mechanistic roles. To determine the molecular regulation of these proteins, we treated male, Sprague-Dawley rats daily by gavage with either vehicle, rosiglitazone (RGZ, 50mg/kg bw), or PD168 (a test compound causing marked edema, 10mg/kg bw), for 1, 3, or 5 days (n=6/treatment/time). On day 1, urine sodium excretion was significantly reduced by RGZ with a strong trend for PD168 (p-values 0.047 and 0.053, respectively) indicating early sodium retention. Blood pressure was lowered by RGZ- or PD168 treatment by 12h. Immunoblotting of whole kidney homogenates (WKHs) and a membrane-enriched fraction (MF) revealed increased band densities for AQP-2 in WKH (29 kDa and glycosylated bands) by both drugs at 1 day. However, at 5 days, the 29-kDa band was significantly decreased ( approximately 30% of vehicle). alpha-ENaC was increased by RGZ at 3 days; however both agents decreased alpha-ENaC by 5 days. In contrast, beta- and gamma-ENaC (85 kDa) were unchanged or decreased at all times by both agents. However, the 70-kDa band of gamma-ENaC (active band) in MF was increased in density (120-600%) by both agents on days 3-5. Overall, both agents resulted in early alterations in banding patterns for AQP-2 and ENaC subunits, many of which are described as activating changes. However, later reduction in AQP-2 and alpha-ENaC may represent an attempt to re-establish sodium and water balance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin / blood
  • Animals
  • Aquaporin 2 / metabolism*
  • Blood Pressure / drug effects
  • Edema / chemically induced*
  • Edema / metabolism*
  • Epithelial Sodium Channels / metabolism*
  • Insulin / blood
  • Kidney / drug effects*
  • Kidney / metabolism*
  • Male
  • Natriuresis / drug effects
  • Oxazoles / toxicity*
  • PPAR gamma / agonists*
  • Rats
  • Rats, Sprague-Dawley
  • Rosiglitazone
  • Thiazolidinediones / toxicity
  • Triazoles / toxicity*
  • Water-Electrolyte Balance / drug effects

Substances

  • Adiponectin
  • Aqp2 protein, rat
  • Aquaporin 2
  • Epithelial Sodium Channels
  • Insulin
  • Oxazoles
  • PD0344168
  • PPAR gamma
  • Thiazolidinediones
  • Triazoles
  • Rosiglitazone