Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 26, Pages 9406-9411Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0501744102
Keywords
roziglitazone; Cre recombinase; Evans blue technique
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Funding
- NHLBI NIH HHS [R01 HL079453, R0-1 HL079453] Funding Source: Medline
- NIDDK NIH HHS [R0-1 DK066592, K01 DK064981, R01 DK066592] Funding Source: Medline
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The peroxisome proliferator-activated receptor subtype gamma (PPAR gamma) ligands, namely the synthetic insulin-sensitizing thiazolidinedione (TZD) compounds, have demonstrated great potential in the treatment of type II diabetes. However, their clinical applicability is limited by a common and serious side effect of edema. To address the mechanism of TZD-induced edema, we generated mice with collecting duct (CD)-specific disruption of the PPAR gamma gene. We found that mice with CID knockout of this receptor were resistant to the rosiglitazone- (RGZ) induced increases in body weight and plasma volume expansion found in control mice expressing PPAR gamma in the CID. RGZ reduced urinary sodium excretion in control and not in conditional knockout mice. Furthermore, RGZ stimulated sodium transport in primary cultures of CD cells expressing PPAR gamma and not in cells lacking this receptor. These findings demonstrate a PPAR gamma- dependent pathway in regulation of sodium transport in the CD that underlies TZD-induced fluid retention.
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