Submitted on August 18, 2008
Revised on September 6, 2008
Accepted on September 15, 2008
Regulation of renal 12(S)-hydroxyeicosatetraenoic acid in diabetes by angiotensin AT1 and AT2 receptors
Emaad M. Abdel-Rahman1, Peter M. Abadir1, and Helmy M. Siragy1*
1 University of Virginia
* To whom correspondence should be addressed. E-mail: hms7a{at}virginia.edu.
Diabetes is associated with increased production of 12(S)- Hydroxyeicosatetraenoic Acid [12(S)-HETE]. The mechanisms involved in this process remain unclear. We hypothesized that hyperglycemia and angiotensin II (Ang) regulates renal 12(S)-HETE production via a balance between angiotensin AT1 and AT2 receptors activities. Using microdialysis technique, renal interstitial fluid (RIF) levels of angiotensin II and 12(S)-HETE were monitored in normal control and streptozotocin induced diabetes rats at baseline, then weekly thereafter for 12 weeks. In a second group of normal and diabetic rats, 3 weeks after development of diabetes, we monitored RIF 12(S)-HETE levels in response to acute AT1 receptor blockade with valsartan or AT2 receptor blockade with PD 123319 individually or combined. Two weeks after induction of diabetes there were 404% increase in Ang II (p<0.05), 149% increase in 12S-HETE (p<0.05) and a 649% increase in urinary albumin excretion (p<0.05). These levels remained elevated throughout the study. PD 123319 given alone had no effect on 12(S)-HETE. Valsartan decreased 12(S)-HETE by 61.6% (p<0.0001), a response that was abrogated when PD 123319 was given with valsartan. These data demonstrate that hyperglycemia increases renal Ang II and 12(S)-HETE levels. The increase in 12(S)-HETE is mediated via AT1 receptor. The attenuation of the effects of AT1 receptor blockade by PD 123319 suggests that AT2 receptor contributes to the down regulation of renal 12(S)-HETE production.
