Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice

Abstract

Oxidative stress is involved in acute kidney injury due to ischemia-reperfusion and chemotherapy-induced nephrotoxicity. To investigate their basic mechanisms we studied the role of nuclear factor-erythroid 2-p45-related factor 2 (Nrf2), a redox-sensitive transcription factor that regulates expression of several antioxidant and cytoprotective genes. We compared the responses of Nrf2-knockout mice and their wild-type littermates in established mouse models of ischemia-reperfusion injury and cisplatin-induced nephrotoxicity. Several Nrf2-regulated genes encoding antioxidant enzymes/proteins were significantly upregulated in the kidneys of wild type but not Nrf2-knockout mice following renal ischemia. Renal function, histology, vascular permeability, and survival were each significantly worse in the Nrf2 knockout mice. Further, proinflammatory cytokine and chemokine expression tended to increase after ischemia in the knockout compared to the wild-type mice. Treatment of the knockout mice with the antioxidants N-acetyl-cysteine or glutathione improved renal function. The knockout mice were more susceptible to cisplatin-induced nephrotoxicity, and this was blunted by N-acetyl-cysteine pretreatment. Our study demonstrates that Nrf2-deficiency enhances susceptibility to both ischemic and nephrotoxic acute kidney injury, and identifies this transcription factor as a potential therapeutic target in these injuries.

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

“…In addition to promoting oxidative stress, impaired Nrf2 function contributes to intra-renal inflammation and progression of kidney disease. In fact ablation of Nrf2 gene results in intensification of oxidative stress, inflammation, and renal injury in diabetic animals [17] and heightens the severity of ischemic and nephrotoxic acute kidney injury [18].…”

Role of Nrf2 Dysfunction in Uremia-Associated Intestinal Inflammation and Epithelial Barrier Disruption

“…The renal protective effect of Nrf2 is supported by the fact that Nrf2 knockout mice develop lupus-like autoimmune nephritis [33] and show intensified oxidative stress with accelerated renal injury when subjected to experimental diabetes mellitus [34]. Further, Nrf2-deficient mice subjected to ischemic and nephrotoxic insults show impaired upregulation of antioxidant pathways, with more severe acute kidney injury and higher mortality, compared to wild-type controls [35]. Finally, recent studies have demonstrated the salutary effects of a low dose of Nrf2 inducer dh404 on oxidative stress, kidney fibrosis, endothelial dysfunction, and vascular abnormalities in CKD animals [36,37].…”

The Effect of Nrf2 on Diabetic Complications

“…Nrf2 deiciency is associated with an increased mortality accompanied by augmented kidney dysfunction and vascular permeability. Liu et al [13] demonstrated that Nrf2 deiciency enhances susceptibility to both ischemic and nephrotoxic acute kidney injury and identiies this transcription factor as a potential therapeutic target in these injuries.…”

“…On the other hand, Nrf2 plays a protective role in experimental acute kidney injury, and this protection is mediated, in part, through an endogenous antioxidant pathway [2,13].…”

“…Experimental and clinical studies have shown the important roles that Nrf2 and its downstream genes play in the pathogenesis of cardiac remodeling and heart failure induced by a number of factors. TNF-α has an important role in a number of pathologies associated with oxidative stress including diabetes, cancer, cardiac hypertrophy, and cardiomyopathy [6,13].…”