The Role of Renal Medullary Bilirubin and Biliverdin Reductase in Angiotensin II-Dependent Hypertension

Abstract

Background Increased circulating bilirubin attenuates angiotensin (Ang) II-induced hypertension and improves renal hemodynamics. However, the intrarenal mechanisms that mediate these effects are not known. The goal of the present study was to test the hypothesis that bilirubin generation in the renal medulla plays a protective role against Ang II-induced hypertension. Methods Twenty-week-old male C57Bl/6J mice were implanted with intrarenal medullary interstitial (IRMI) catheters following unilateral nephrectomy. After this time, biliverdin IXα was specifically infused into the kidney (3.6 mg/day) for 3 days before implantation with an osmotic minipump delivering Ang II (1000 ng/kg/min). BP was recorded for 3 days, 1 week after minipump infusion, in conscious mice. To further explore the antihypertensive role of renal medullary bilirubin generation, mice with specific deletion of biliverdin reductase-A (Blvra) in the thick ascending loop of Henle (TALH) were generated. At 20 weeks, BlvraTALHKO and control mice (Blvrafl/fl) were infused with Ang II for 2 weeks. Results IRMI infusion of biliverdin significantly decreased blood pressure compared to mice infused with vehicle (118 ± 4 vs. 158 ± 2 mmHg, p<0.05). Angiotensin-II infusion resulted in significantly higher blood pressure measured in conscious mice 7 days after implantation in BlvraTALHKO as compared to Blvrafl/fl mice (152 ± 2 vs. 140 ± 3 mmHg, p<0.05). Conclusions Together, these findings show that medullary bilirubin and biliverdin reductase can improve hypertension and that mechanisms that increase bilirubin and biliverdin reductase in the renal medulla could be an effective approach to treat hypertension.