I have been studying prostaglandins and other lipid-derived mediators that regulate renal function for a long time. Over the years, we have defined the role of COX- 2/mPGES-1/PGE2-mediated prostaglandin pathway, nuclear receptors PPARgamma and liver X receptor, and nitro-oleic acid in renal health and disease. Our recent work has demonstrated an important interplay between the lipid mediators and (pro)renin receptor-mediated intrarenal renin-angiotensin system after the demonstration that renal PRR and intrarenal renin are under the control of COX-2/EP4 pathway. Our results suggest that (pro)renin receptor serves as a common downstream pathway leading to fine-tuning urinary Na+ and water excretion and long-term control of blood pressure. The seminal discoveries include the following: 1) activation of PRR with prorenin but not renin stimulates epithelial Na+ channel, 2) PRR controls the in vivo renin activity, ENaC and aquaporin- 2 expression in the collecting duct, 3) deletion of collecting duct PRR results in diabetes insipidus and downregulation of aqoporine-2, 4) soluble PRR (sPRR) stimulates renal aquoporine-2 and urine concentrating capability, and 5) site-1 protease (S1P) but not furin or ADAM19 contributes to the generation of sPRR. During the past 5 years, we have published 22 papers on this topic in highly prestigious journals such as PNAS, JASN, Hypertension, etc. In 2016, I was selected to deliver Lewis K. Dahl Memorial Lecture at the Council on Hypertension in Orlando. My research program has been well funded by extramural grants. During this reporting period, I have received multiple NIH RO-1 grants and a Merit Review Award with total costs exceeding $10M. The recent submission of the renewal application of the Merit Award has been selected for funding. I have published a total of 161 peer-reviewed articles and delivered more than 100 lectures all over the world. Our work is highly relevant to the VA mission since a significant number of veterans are affected by hypertension and renal disease for which PRR is believed to play a major role and may serve as a novel target for new drug development. Importantly, my research has high translational potential in the areas of chronic kidney disease (CKD) and metabolic disease. I have developed multiple technologies at various stages from preclinical evaluation to Phase II clinical trial for treatment of these diseases. So far, I holds 5 patents with 3 on the use of nitro-oleic acid for the treatment of CKD and metabolic disease and 1 on the similar therapeutic use of sPRR. The nitro-oleic acid technology was licensed to Complexa, Inc, a biotech company that has successfully completed multiple Phase I clinical trials on nitro-oleic acid (commercialized as CXA-10), raised $100 million, and launched a Phase II clinical trial with CXA-10 in 2018. A second technology related to the development of a recombinant soluble PRR as an insulin-sensitizing agent is currently under preclinical evaluation. Novo Nordisk has expressed strong interest in this technology and is performing internal validations. Recently, the mid-term progress report for my RCS was rated excellent with the scores of 1.25 from primary reviewer and 1.1 from the secondary reviewer.
The important role of renin-angiotensin-aldosterone system in the pathogenesis of hypertension and renal disease is highlighted by the wide use of its inhibitors for treatment of these diseases which affect a significant part of veteran?s population. The current research plan will address the role of renal site-1 protease/soluble (pro)renin receptor/AT1R pathway in the disease processes. The proposal has the potential to advance our understanding of the fundamental mechanism of hypertension and also to identify a novel target for antihypertensive therapies.