Previous research has demonstrated that kidney specific induction of heme oxygenase (HO)-1 can attenuate the development of hypertension;however, the specific role of biliverdin reductase (BVR) mediated bilirubin production to this effect has yet to be determined. Biliuribin is one of the most powerful antioxidants in the body. I not only can directly scavenge superoxide anion but it also has been reported to directly inhibit superoxide production through effects on NAD(P)H oxidases. Knockdown of BVR to a level which decreased the intracellular bilirubin generation by 50% was found to significantly increase angiotensin (Ang) II mediated superoxide production in cultured mouse thick ascending loop of Henle (TALH). This project will examine the role of intracellular bilirubin generation in the renal TALH and collecting duct (CD) in modulating renal-pressure natriuresis and blood pressure regulation. Conditional BVR knockout models developed using Cre-lox technology will be used to test the central hypothesis that intracellular bilirubin generation decreases reactive oxygen species (ROS), decreases sodium reabsorption in the TALH and CD through unique mechanisms, restores pressure natriuresis and lowers blood pressure in Ang II and deoxycorticosterone (DOCA)-salt hypertensive mice. To test this hypothesis a combination of whole animal integrative physiology as well as molecular, cellular, and genomic techniques will be used in both Ang II and DOCA-salt hypertensive mice. The research proposed is significant because it will provide new insights into the role of intracellular generated bilirubin in the TALH and CD in the regulation of renal pressure-natriuresis and the development of hypertension. These studies will be the first to specifically determine the role BVR in the regulation of renal pressure natriuresis and will provide an understanding of the role of bilirubin generation to the antihypertensive actions of HO-1 induction in the renal medulla. The results obtained from these studies will expand our knowledge about the function of BVR, the importance of intracellular bilirubin generation and could provide novel therapeutic options for certain hypertensive patient populations who are resistant to current therapies. In addition to increasing our knowledge of bilirubin action as a potential antihypertensive agent these studies will increase the applicant's understanding of whole animal integrative physiology as well as state of the art molecular, cellular, and genomic techniques. The specific role of BVR and intracellular bilirubin generation in the TALH and CD to ROS generation and blood pressure regulation will be addressed in two specific aims: 1. To test the hypothesis that chronic decreases in TALH or CD BVR exacerbates Ang II dependent hypertension via increases in Ang II mediated ROS which alters the renal pressure natriuresis relationship. 2. To test the hypothesis that chronic decreases in TALH or CD BVR exacerbates DOCA-salt dependent hypertension via increases in ROS which alters the renal pressure natriuresis relationship.
Hypertension has long been recognized as a major risk factor for cardiovascular diseases, including coronary artery disease, heart failure and stroke, and for end stage renal disease. In the southeastern United States, and especially in Mississippi, cardiovascular and renal diseases occur much more frequently than in the rest of the country. The objective of this training NRSA is to train and mentor Dr. Peter Hosick in cardiovascular and renal research. In particular, Peter will receive research training in integrative cardiovascular and renal physiology of hypertension. Peter will also be trained to incorporate genomic, integrative physiological and biochemical techniques to clinically relevant problems such as the pathophysiology and treatment of hypertension.