Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease

Abstract

Oxidative stress and inflammation play a central role in progression and complications of CKD and are, in part, due to impairment of the Nrf2 system which regulates expression of antioxidant and detoxifying molecules. Natural Nrf2 inducing phytochemicals have been shown to ameliorate kidney disease in experimental animals. However due to adverse outcomes clinical trial of synthetic Nrf2 activator, bardoxolone methyl (BARD), in CKD patients was terminated. BARD activates Nrf2 via 2 covalent modification of reactive cysteine residues in Nrf2 repressor molecule, Keap-1. In addition to Nrf2, Keap1 suppresses IKKB, the positive regulator of NF k B. Treatment with BARD analog, dh404, at 5-20 mg/kg/day in diabetic obese Zucker rats exacerbates whereas its use at 2 mg/kg/day in 5/6 nephrectomized rats attenuates CKD progression. We, therefore, hypothesized that deleterious effects of high dose BARD are mediated by activation of NF k B.CKD (5/6 nephrectomized) rats were randomized to receive dh404 (2 or 10mg/kg/day) or vehicle for 12 weeks. Vehicle-treated group exhibited glomerulosclerosis, interstitial fibrosis and inflammation, activation of NF k B, upregulation of oxidative, inflammatory and fibrotic pathways, and suppression of Nrf2 activity and its key target gene products. Treatment with low dose dh404 restored Nrf2 activity and expression of its target genes, attenuated activation of NF k B and fibrotic pathways, and reduced glomerulosclerosis, interstitial fibrosis and inflammation. In contrast treatment with high dh404 dosage intensified proteinuria, renal dysfunction and histological abnormalities, amplified up-regulations of NF k B and fibrotic pathways, and suppression of Nrf2 system. Thus therapy with BARD analogs exerts a dose-dependent dimorphic impact on CKD progression.

Downregulation of Nuclear Factor Erythroid 2–Related Factor and Associated Antioxidant Genes Contributes to Redox-Sensitive Vascular Dysfunction in Hypertension

“…23 On the other hand, in Zucker diabetic fatty rats, a model of type 2 diabetes mellitus with progressive renal disease treatment with RTA 405, a bardoxolone analogue, caused worsening of proteinuria, glomerulosclerosis, and tubular damage. 24,25 Clinical studies have also shown discordant results. In the phase II Trial to Determine the Effects of Bardoxolone Methyl on eGFR in Patients With Type 2 Diabetes and Chronic Kidney Disease (BEAM study), patients with chronic kidney disease treated with bardoxolone had significantly improved renal function.…”

“…27 Reasons for these dimorphic findings may relate, in part, to the doses of drugs used as suggested in studies of chronic kidney disease, where the bardoxolone analogue, dh404, at low doses restored Nrf2 activity and reduced glomerulosclerosis, whereas at high doses intensified proteinuria and aggravated renal dysfunction and kidney fibrosis. 25,28 A few studies have shown that Nrf2 is dysregulated in models of hypertension and that Nrf2 activators prevent blood pressure elevation. In mice with renal dopamine 2 receptor deficiency, elevated blood pressure and reduced renal Nrf2 expression were normalized by bardoxolone.…”

Internal Pudental Artery Dysfunction in Diabetes Mellitus Is Mediated by NOX1-Derived ROS-, Nrf2-, and Rho Kinase–Dependent Mechanisms

“…38 However, some studies demonstrated deleterious effects of Nrf2. The Nrf2 activator bardoxolone worsened proteinuria, glomerulosclerosis, and tubular damage in a model of type 2 DM, 39,40 as well as renal function in a phase II clinical trial. 41 In addition, a trial was prematurely terminated because of higher incidence of heart failure and mortality in bardoxolone-treated patients.…”

“…42 Additional studies demonstrated that although low doses of Nrf2 activators are protective, high doses lead to deleterious outcomes. 40,43 In basal conditions, Keap1, which regulates Nrf2 ubiquitination via Cul3-Keap1, keeps Nrf2 in the cytosol. In oxidative stress conditions, it is expected that Cul3-Keap1-E3 ligase is inhibited by oxidation, releasing Nrf2, which translocates to the nucleus, binds to antioxidant response element, and initiates transcription of antioxidant enzymes.…”

“…42 Additional studies demonstrated that although low doses of Nrf2 activators are protective, high doses lead to deleterious outcomes. 40,43 In basal conditions, Keap1, which regulates Nrf2 ubiquitination via Cul3-Keap1, keeps Nrf2 in the cytosol. In oxidative …”