Submitted on March 6, 2008
Accepted on October 20, 2008
Increased renal adrenomedullin expression in rats with ureteral obstruction
Rikke Norregaard1, Tina Boedker1, Boye L. Jensen2, Lene Stoedkilde1, Soren Nielsen3, and Jorgen Frokiaer4*
1 The Water and Salt Research Center, University of Aarhus, Aarhus N, Denmark; Institute of Clinical Medicine, University of Aarhus, Aarhus N, Denmark
2 Physiology and Pharmacology, University of Southern Denmark, Odense C, Denmark
3 The Water and Salt Research Center, University of Aarhus, United States
4 The Water and Salt Research Center, University of Aarhus, Denmark
* To whom correspondence should be addressed. E-mail: jf{at}ki.au.dk.
Ureteral obstruction is characterized by decreased renal blood flow that is associated with hypoxia within the kidney. Adrenomedullin (AM) is a peptide hormone with tissue-protective capacity which is stimulated through hypoxia. We tested the hypothesis that ureteral obstruction stimulates expression of AM and hypoxia-inducible factor-1 (HIF-1
) in kidneys. Rats were exposed to bilateral ureteral obstruction (BUO) for 2, 6, 12 and 24 hours or SHAM operation and compared to unilateral obstruction (UUO). AM mRNA expression was measured by QPCR in cortex and outer medulla (C+OM) and inner medulla (IM). AM and HIF-1 protein abundance and localization were determined in rats subjected to 24hBUO. AM mRNA expression in C+OM increased significantly after 12h BUO and further increased after 24h. In IM, AM mRNA expression increased significantly in response to BUO for 6h and further increased after 24h. AM peptide abundance was enhanced in C+OM and IM after 24h BUO. Immunohistochemical labeling of kidneys showed a wider distribution and more intense AM signal in 24h BUO compared to SHAM. In UUO rats, AM mRNA expression increased significantly in IM of the obstructed kidney compared to non-obstructed and SHAM kidney while AM peptide increased in IM compared to SHAM. HIF-1 protein abundance increased significantly in IM after 24hBUO compared to SHAM and HIF-1 immunoreactive protein co-localized with AM. In summary, AM and HIF-1 expression increase in response to ureteral obstruction in agreement with expected oxygen gradients. Hypoxia acting through HIF-1 accumulation may be an important pathway for the renal response to ureteral obstruction.
