Protective effects of nitro-oleic acid in hypertensive chronic kidney injury

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

? DESCRIPTION (provided by applicant): 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.