UC Irvine

This research proposal outlines preclinical pharmacological approaches to elucidate the potential efficacy of Nrf2 activation to ameliorate diabetic kidney disease (DKD). A key vulnerability of the kidney in diabetes stems from its functional reliance on mitochondrial energetics and its susceptibility to oxidative stress. The focus on Nrf2 is linked to this transcription factor’s induction of several antioxidant genes upon activation. The goals of this proposal are thus twofold. First, I seek to demonstrate target engagement of the novel small molecule Nrf2 activator, leading to improvement in functional and histological endpoints in an animal model of DKD. Next, I will evaluate whether selective Nrf2 agonism avoids adverse effects on the endothelin signaling pathway in a preclinical model of DOCA-salt nephropathy. This adverse effect, which can lead to heart failure, was seen in a subset of patients in clinical trials with the nonspecific Nrf2 activator Bardoxolone methyl. The ultimate purpose of this initiative is the development of effective strategies for prevention and management of human diabetic nephropathy, a renal disease demonstrating insufficient activation of the antioxidant stress response. The potential translational impact of this approach is high, as the Nrf2 activator Bardoxolone methyl has already demonstrated efficacy in mild to moderate DKD in clinical trials, though it has demonstrated toxic side effects in advanced DKD. To accomplish these goals, I propose three projects to demonstrate: (1) Nrf2 Dysregulation in a Preclinical Model of DKD; (2) Target Engagement and Functional/Histological Improvement in a Preclinical Model of DKD with an Orally Dosed Small Molecule Nrf2 Activator; and (3) Lack of Toxic Liabilities of an Orally Dosed Specific Small Molecule Nrf2 Activator that are Otherwise Associated with Bardoxolone Methyl Treatment, a Nonspecific Nrf2 Activator.