Kidney Week

Abstract: TH-OR79

Renal Medullary Bilirubin and Biliverdin Reductase Attenuate Angiotensin II-Induced Hypertension

Session Information

• Hypertension and CVD: Research Advances
  October 24, 2024 | Location: Room 5, Convention Center
  Abstract Time: 05:30 PM - 05:40 PM

Category: Hypertension and CVD

• 1601 Hypertension and CVD: Basic

Authors

• Arthur, Gertrude, University of Mississippi Medical Center Holmes County, Jackson, Mississippi, United States

Gertrude Arthur, PhD

• Stec, David E., University of Mississippi Medical Center Holmes County, Jackson, Mississippi, United States

David E. Stec, PhD

Group or Team Name

• Stec Lab.

Background

Hypertension is a risk factor for CKD and despite the major advances in drug development to target this disease, uncontrolled blood pressure is a significant problem among hypertensive patients. An increase in circulating bilirubin has been shown to attenuate angiotensin (Ang) II-induced hypertension and improve renal hemodynamics. However, the intrarenal mechanisms that mediate the anti-hypertensive effects of bilirubin are not yet known. The goal of the present study was to test the hypothesis that generation of bilirubin in the renal medulla plays an important role in the regulation of blood pressure (BP) in response to Ang II.

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 prior to 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 (BVRA) in the thick ascending loop of Henle (TALH) were generated by crossing BVRA^flox/flox mice with Tamm-Horsfall Cre (THP-Cre) mice. At 20 weeks, THP-Cre/BVRA^flox/flox and control mice were infused with Ang II for 2 weeks.

Results

IRMI infusion of biliverdin significantly decreased BP as compared to mice infused with vehicle (118 + 4 vs. 158 + 2 mmHg, p<0.05, n=6/group). THP-Cre/BVRA^flox/flox mice did not exhibit any differences in baseline BP as compared to BVRA^flox/flox mice (108 + 2 vs. 108 + 2 mmHg, n=5/group). However, Ang-II infusion resulted in significantly higher BP measured in conscious mice 7 days after implantation in THP-Cre/BVRA^flox/flox as compared to BVRA^flox/flox mice (152 + 2 vs. 140 + 3 mmHg, p<0.05, n=5/group). Also, protein expression of renal outer medullary potassium (ROMK) channel was increased in THP-Cre/BVRA^flox/flox mice infused with Ang II (1.05 + 0.09 vs. 0.7 + 0.20 AU, p<0.05, n=4/group)

Conclusion

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.

Funding

• NIDDK Support