A vicious cycle of inflammation and reduction-oxidation imbalance has recently been discovered as a critical aberration in a variety of chronic disease, including chronic kidney disease (CKD). In particular, the biomechanical, hormonal, and inflammatory insults to the kidney in the context of hypertension converge on production of reactive species and culminate in adverse fibrotic remodeling. Reactive species act not only as chemical agents indiscriminately damaging cellular constituents, but also as signaling molecules instigating highly specific changes in cellular behavior and differentiation. We have previously demonstrated that electrophilic nitro-fatty acids upregulate cytoprotective responses and allow cells to cope with oxidative insult. This family of compounds has also been shown to be tolerogenic, reducing leukocyte extravasation and cytokine production in macrophages. Our new preliminary data indicate that orally-administered nitro-oleic acid (NO2-OA) has renal protective effects in a deoxycorticosterone (DOCA)-salt model of murine hypertension. In this proposal, I seek to identify the mechanisms by which NO2-OA affords renal protection in hypertensive kidney injury. Specifically, I will investigate the therapeutic efficacy of NO2-OA on (1) hypertension-induced inflammatory response in the renal parenchyma and (2) antioxidant gene expression in renal fibrotic remodeling. Beyond evaluating a promising pharmacological candidate, the proposed studies will yield fundamental understanding of the role of reduction- oxidation imbalance in CKD. Overall, these studies will provide new functional and mechanistic insights into the pathogenesis of chronic kidney failure, and have the potential to uncover two novel pharmacologic strategies for treatment of this epidemic disease.
Chronic kidney disease (CKD) is the 9th leading cause of death in the US. In 2011 alone, CKD was responsible for 92,000 deaths and cost $34 billion in healthcare expenditures. While high blood pressure affects one in three Americans and is the second leading cause of CKD, only half of hypertensives receive adequate medical management. Thus, blood pressure control falls short as a mainstay of prevention. This observation highlights the need for innovative approaches for preventing or treating CKD, including strategies to reduce renal inflammation and structural remodeling caused by hypertension. Using highly-relevant animal models of hypertension, rigorous in vitro studies of fibrogenic signaling, and unambiguous analytical methods, this proposal seeks to define the key interactions between inflammatory cell infiltration, reduction-oxidation imbalance, and fibrogenic changes, all under the umbrella of therapeutic intervention with electrophilic nitro- fatty acids. The results of this study will directly contribute to the conceptual advancement and practical development of disease-modifying strategies using electrophilic lipid mediators for hypertensive CKD.
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