Transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2) ameliorates sepsis-associated acute kidney injury by maintaining mitochondrial homeostasis and improving the mitochondrial function

Abstract

Mitochondrial dysfunction has a role in sepsis-associated acute kidney injury (S-AKI), so the restoration of normal mitochondrial homeostasis may be an effective treatment strategy. Transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2) is a main regulator of cell-redox homeostasis, and recent studies reported that NRF2 activation helped to preserve mitochondrial morphology and function under conditions of stress. However, the role of NRF2 in the process of S-AKI is still not well understood. The present study investigated whether NRF2 regulates mitochondrial homeostasis and influences mitochondrial function in S-AKI. We demonstrated activation of NRF2 in an in vitro model: lipopolysaccharide (LPS) challenge of ductal epithelial cells of rat renal tubules (NRK-52e cells), and an in vivo model: cecal ligation and puncture (CLP) of rats. Over-expression of NRF2 attenuated oxidative stress, apoptosis, and the inflammatory response; enhanced mitophagy and mitochondrial biogenesis; and mitigated mitochondrial damage in the in vitro model. In vivo experiments showed that rats treated with an NRF2 agonist had higher adenosine triphosphate (ATP) levels, lower blood urea nitrogen and creatinine levels, fewer renal histopathological changes, and higher expression of mitophagy-related proteins [PTEN-induced putative kinase 1 (PINK1), parkin RBR E3 ubiquitin protein ligase (PRKN), microtubule-associated protein 1 light chain 3 II (LC3 II)] and mitochondrial biogenesis-related proteins [peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1α) and mitochondrial transcription factor A (TFAM)]. Electron microscopy of kidney tissues showed that mitochondrial damage was alleviated by treatment with an NRF2 agonist, and the opposite response occurred upon treatment with an NRF2 antagonist. Overall, our findings suggest that mitochondria have an important role in the pathogenesis of S-AKI, and that NRF2 activation restored mitochondrial homeostasis and function in the presence of this disease. This mitochondrial pathway has the potential to be a novel therapeutic target for the treatment of S-AKI.

Advances in metabolic reprogramming of renal tubular epithelial cells in sepsis-associated acute kidney injury

“…Frontiers in Physiology frontiersin.org stress, and apoptosis (Chen et al, 2022). These findings collectively underscore the significance of mitochondrial biogenesis in the recovery process of TECs post-injury.…”

Cuproptosis-Related Biomarkers and Characterization of Immune Infiltration in Sepsis

“…[16][17][18] The application of mitochondrial protectors can reduce the effects of sepsis-mediated organic damage. 19 In summary, we deduced that cuproptosis is closely related to sepsis-induced multi-organ damage. However, no studies have been reported to date on the mechanisms regulating copper death in the development of sepsis, and further insightful research is needed.…”

The Long Noncoding RNA Cytoskeleton Regulator RNA (CYTOR)/miRNA-24-3p Axis Facilitates Nasopharyngeal Carcinoma Progression by Modulating GAD1 Expression

“…Written consents were signed by the patients, and the study protocol was approved by the ethics committee of Nanchong Central Hospital in accordance with the Declaration of Helsinki. For immunohistochemistry analysis, the samples embedded in paraffin were cut into sections of 5 β M. The following procedures were conducted as reported [ 27 , 28 ]. Briefly, sections were dewaxed and heat-treated to retrieve epitopes by immersing in a citrate buffer solution at pH 6.0 in an autoclave at 121°C for 1 min.…”

“…For immunohistochemistry analysis, the samples embedded in parafn were cut into sections of 5 βM. Te following procedures were conducted as reported [27,28]. Briefy, sections were dewaxed and heat-treated to retrieve epitopes by immersing in a citrate bufer solution at pH 6.0 in an autoclave at 121 °C for 1 min.…”