Role of Nrf2 in protection against acute kidney injury

Abstract

Multifaceted cell defense pathways perform a critical role in the maintenance of homeostasis at the cellular, tissue, and organism levels. The Keap1-Nrf2 pathway is one of the most important of these cytoprotective pathways, with Nrf2 serving as a master transcriptional regulator of the basal and inducible expression of a multitude of genes encoding detoxification enzymes, antioxidant proteins, xenobiotic transporters, and other stress-response mediators. An increasing body of evidence supports a vital physiological role for Nrf2 in protection of the kidney against a number of diseases, and the pharmacological induction of Nrf2 by bardoxolone methyl (methyl-2-cyano 3,12-dioxooleano-1,9-dien-28-oate, CDDO-Me) has shown promise for the management of such pathologies. Acute kidney injury, induced by drugs and other stimuli, is a significant clinical problem, and accounts for the cessation of development of many promising drug candidates. A better understanding of the molecular mechanisms that underlie acute kidney injury, and the biological facets that determine the balance between renal adaptation and dysfunction, is therefore vital to reducing clinical burden and patient suffering. The focus of this review is to highlight recent work that has demonstrated an ability of Nrf2 to determine the sensitivity of the kidney to acute injury invoked by environmental insults such as heavy metals and ischemia, as well as xenobiotics such as cyclosporin A and cisplatin.

Proximal Tubules Have the Capacity to Regulate Uptake of Albumin

“…Multiple studies have documented that induction of Nrf2 is protective for the kidney in CKD, diabetic nephropathy, renal fibrosis, ischemia and other insults. 52 The fact that this was inhibited suggests the acute overload model does not induce stress nor needs the stress response elements increased, thus preventing an over-reaction to this acute protein load. The second upstream regulator inhibited was ANGPT2.…”

“…First, NFE2L2 encodes the protein Nrf2, which is part of the cytoprotective Keap1-Nrf2 pathway. 52 Normally repressed by its association with Keap1-Cul3 complex in the cytoplasm, Nrf2 migrates to the nucleus upon stress induction and binds to specific response elements inducing expression of target genes to detoxify, provide oxidant protection, and other stress response mediators. Multiple studies have documented that induction of Nrf2 is protective for the kidney in CKD, diabetic nephropathy, renal fibrosis, ischemia and other insults.…”

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).…”

Lithium in the Kidney: Friend and Foe?

“…[107][108][109][110][111] Although the involved mechanisms are poorly studied, they might involve GSK3-mediated degradation of the transcription factor Nrf2, which upregulates the expression of different antioxidant proteins, like Bcl-2, and recently emerged as an important player in protection against AKI. [112][113][114][115][116] …”