Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage progression

Abstract

Acute kidney injury is a devastating disease with high morbidity in hospitalized patients and contributes to the pathogenesis of chronic kidney disease. An underlying mechanism of acute kidney injury involves ischemia-reperfusion injury which, in turn, induces oxidative stress and provokes organ damage. Nrf2 is a master transcription factor that regulates the cellular response to oxidative stress. Here, we examined the role of Nrf2 in the progression of ischemia-reperfusion injury-induced kidney damage in mice using genetic and pharmacological approaches. Both global and tubular-specific Nrf2 activation enhanced gene expression of antioxidant and NADPH synthesis enzymes, including glucose-6-phosphate dehydrogenase, and ameliorated both the initiation of injury in the outer medulla and the progression of tubular damage in the cortex. Myeloid-specific Nrf2 activation was ineffective. Short-term administration of the Nrf2 inducer CDDO during the initial phase of injury ameliorated the late phase of tubular damage. This inducer effectively protected the human proximal tubular cell line HK-2 from oxidative stress-mediated cell death while glucose-6-phosphate dehydrogenase knockdown increased intracellular reactive oxygen species. These findings demonstrate that tubular hyperactivation of Nrf2 in the initial phase of injury prevents the progression of reactive oxygen species-mediated tubular damage by inducing antioxidant enzymes and NADPH synthesis. Thus, Nrf2 may be a promising therapeutic target for preventing acute kidney injury to chronic kidney disease transition.

Stress-sensing mechanisms and the physiological roles of the Keap1–Nrf2 system during cellular stress

“…Even if treatment includes chronic administration of potent Nrf2 inducers, the body does not seem to be impaired. Indeed, many previous studies revealed that pharmacological Nrf2 activation has a protective effect on a variety of stress-mediated diseases, including kidney injury (80,81).…”

Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression

“…We recently investigated the roles that NRF2 plays in preventing kidney disease progression from AKI to CKD using a unilateral IRI mouse model [60]. We found that, compared to the contralateral uninjured kidneys, injured kidneys slightly induce the expression of NRF2 target genes within 24 h after injury and accumulate ROS and electrophiles.…”

“…2). The damaged area expands to the cortex, and the kidney mass is reduced after day 5, with the infiltration of inflammatory cells and tubular cell death [60]. On day 14, most of the remaining tubules are damaged, and progressive fibrosis is observed in the interstitium (Fig.…”

“…2). These results suggest that IRI induces the progression of kidney damage from AKI to CKD within 2 weeks after injury [60]. …”

Role of bardoxolone methyl, a nuclear factor erythroid 2-related factor 2 activator, in aldosterone- and salt-induced renal injury

“…19 Their renoprotective effects have been verified using Nrf2-deficient mice in, for instance, diabetic nephropathy, 20 lupus-like autoimmune nephritis 21 and ischemic reperfusion injury. 22 Bardoxolone methyl (BM), one such Nrf2 activator, has been reported in clinical practice to have a beneficial effect on the renal function of patients with type 2 diabetic nephropathy. 23 In hypertension models, Nrf2 activators were reported to be related to improvement of vascular function via antioxidant property.…”