Abstract P266: Thromboxane-prostanoid Receptors (tp-rs) Mediate Hypertension, H2o2 Generation and Impaired Renal Afferent Arteriolar Myogenic Responses Leading to Nephropathy in Doca/salt Mice

Abstract

Background: DOCA/uninephrectomy/high salt (DOCA) is a model of hypertensive nephropathy. Afferent arteriolar myogenic responses prevent hypertensive renal barotrauma but myogenic tone is blocked by vascular generation of H 2 O 2 . Since thromboxane-prostanoid receptors (TP-Rs) generate H 2 O 2 , we tested the hypothesis that they mediate hypertensive nephropathy. Methods: DOCA and Sham TP-R +/+ and -/- mice (n=6/group) were studied at 2 weeks and myogenic responses recorded from the diameter of perfused single afferent arterioles studied in a bath preparation during increased perfusion pressure (40 to 80 mmHg). Results: DOCA treatment in TP-R +/+ mice increased (p<0.001) 24-hour excretion of H 2 O 2 (45 ± 3 vs 220 + 15 nmol) , TxB 2 (4 ± 2 vs 29 ± 4 pmol) and albumin (20 ± 5 vs 270 ± 20 mg) and increased MAP by 35 ± 5 mmHg. However, all effects of DOCA were prevented in TP-R -/- mice. Sham treatment had no effect in TPR +/+ or -/- mice. Myogenic responses were severely impaired in DOCA vs sham WT mice (Δ diameter: -4 ± 1 vs -8 ± 1%; p< 0.005). Myogenic responses also were reduced by incubation of arterioles with 10 -10 mol·l -1 of the TP-R mimetic, U-46,619 vs vehicle added to the bath for 10 minutes (Δ diameter: -7 ± 1 vs -10 ± 1%; p<0.01) and in WT mice infused for 3 days with U-46,619 (500 ng·kg -1 ·d -1 x 3) vs vehicle (Δ diameter: -3 ± 1 vs -10 ± 1%; p<0.005). Conclusion: Hypertensive nephropathy is dependent on TP-Rs that mediate the increase in H 2 O 2 and blood pressure and likely the impaired myogenic responses that expose the kidney to barotrauma