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.

Public Health Relevance

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.

National Institute of Health (NIH)
Veterans Affairs (VA)
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VA Salt Lake City Healthcare System
Salt Lake City
United States
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