Moderate hyperbilirubinemia improves renal hemodynamics in ANG II-dependent hypertension.
We have previously demonstrated that moderate hyperbilirubinemia decreases blood pressure in ANG II-dependent hypertension through mechanisms that decrease oxidative stress and increase nitric oxide levels. Since decreases in renal hemodynamics play an important role in mediating the hypertensive actions of ANG II, the goal of the present study was to examine the effect of moderate hyperbilirubinemia on glomerular filtration rate (GFR) and renal blood flow (RBF) in a mouse model of ANG II hypertension. Mice were made moderately hyperbilirubinemic by two methods: indinavir or specific morpholino antisense oligonucleotides against UGT1A1, which is the enzyme responsible for the conjugation of bilirubin in the liver. GFR and RBF were measured in mice after implantation of an osmotic minipump delivering ANG II at a rate of 1 μg·kg(-1)·min(-1). GFR was measured by continuous infusion of I(125)-labeled iothalamate on days 5 and 6 of ANG II infusion in conscious mice. RBF was measured on day 7 of ANG II infusion in anesthetized mice. Blood levels of unconjugated bilirubin were significantly increased in mice treated with indinavir or anti-UGT1A1 (P = 0.002). ANG II decreased GFR by 33% of control (n = 9, P = 0.004), and this was normalized by moderate hyperbilirubinemia (n = 6). Next, we examined the effect of moderate hyperbilirubinemia on RBF in ANG II-infused mice. ANG II infusion significantly decreased RBF by 22% (P = 0.037) of control, and this decrease was normalized by moderate hyperbilirubinemia (n = 6). These results indicate that improvement of renal hemodynamics may be one mechanism by which moderate hyperbilirubinemia lowers blood pressure in this model.
Vera
Trinity
T
Dept. of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, 39216-4505, USA.
Stec
David E
DE
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D001663:Bilirubin / Q000097:blood; D015153:Blotting, Western; D005919:Glomerular Filtration Rate / Q000502:physiology; D014453:Glucuronosyltransferase / Q000378:metabolism; D006932:Hyperbilirubinemia / Q000503:physiopathology*; D006973:Hypertension / Q000503:physiopathology*; D019469:Indinavir / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012079:Renal Circulation / Q000502:physiology*
D009025:Morpholines; C464433:Oatp2 protein, mouse; D016376:Oligonucleotides, Antisense; D027701:Organic Cation Transport Proteins; D011500:Protein Synthesis Inhibitors; D000804:Angiotensin II; D019469:Indinavir; D014453:Glucuronosyltransferase; D001663:Bilirubin