Integrated transcriptomic and proteomic analyses uncover regulatory roles of Nrf2 in the kidney

Shelton, Luke M.; Lister, Adam; Walsh, James; Jenkins, Rosalind E.; Wong, Michael H. L.; Rowe, Cliff; Ricci, Emanuele; Ressel, Lorenzo; Fang, Yongxiang; Demougin, Philippe; Vukojević, Vanja; O’Neill, Paul M.; Goldring, Christopher E.; Kitteringham, Neil R.; Park, B. Kevin; Odermatt, Alex; Copple, Ian M.

doi:10.1038/ki.2015.286

Cited by 46 publications

(33 citation statements)

References 48 publications

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“…Nrf2 is a major transcription factor that induces the expression of antioxidant enzymes including those responsible for glutathione synthesis. Activation of Nrf2 has been implicated as a potential therapeutic target in kidney disease [48–50]. In the present study, renal IR resulted in a significant decrease in Nrf2 protein level in the nucleus.…”

Section: Discussionsupporting

confidence: 56%

Downregulation of Glutathione Biosynthesis Contributes to Oxidative Stress and Liver Dysfunction in Acute Kidney Injury

Shang

Siow

Isaak

et al. 2016

Oxidative Medicine and Cellular Longevity

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Ischemia-reperfusion is a common cause for acute kidney injury and can lead to distant organ dysfunction. Glutathione is a major endogenous antioxidant and its depletion directly correlates to ischemia-reperfusion injury. The liver has high capacity for producing glutathione and is a key organ in modulating local and systemic redox balance. In the present study, we investigated the mechanism by which kidney ischemia-reperfusion led to glutathione depletion and oxidative stress. The left kidney of Sprague-Dawley rats was subjected to 45 min ischemia followed by 6 h reperfusion. Ischemia-reperfusion impaired kidney and liver function. This was accompanied by a decrease in glutathione levels in the liver and plasma and increased hepatic lipid peroxidation and plasma homocysteine levels. Ischemia-reperfusion caused a significant decrease in mRNA and protein levels of hepatic glutamate-cysteine ligase mediated through the inhibition of transcription factor Nrf2. Ischemia-reperfusion inhibited hepatic expression of cystathionine γ-lyase, an enzyme responsible for producing cysteine (an essential precursor for glutathione synthesis) through the transsulfuration pathway. These results suggest that inhibition of glutamate-cysteine ligase expression and downregulation of the transsulfuration pathway lead to reduced hepatic glutathione biosynthesis and elevation of plasma homocysteine levels, which, in turn, may contribute to oxidative stress and distant organ injury during renal ischemia-reperfusion.

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Section: Discussionsupporting

confidence: 56%

Downregulation of Glutathione Biosynthesis Contributes to Oxidative Stress and Liver Dysfunction in Acute Kidney Injury

Shang

Siow

Isaak

et al. 2016

Oxidative Medicine and Cellular Longevity

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“…These genes include members of the glutathione-S-transferase family ( GSTM1 and GSTP1 ) and NAD(P)H: quinone oxidoreductase 1 ( NQO1 ), which play roles in detoxification and in preventing oxidative stress202122.…”

Section: Resultsmentioning

confidence: 99%

Keap1 hypomorphism protects against ischemic and obstructive kidney disease

Tan

Chartoumpekis

Rush

et al. 2016

Sci Rep

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The Keap1/Nrf2 pathway is a master regulator of antioxidant, anti-inflammatory, and other cytoprotective mechanisms important in protection from kidney disease. For the first time in kidney disease, we describe the use of Keap1 hypomorphic mice, which possess Nrf2 hyperactivation. We exposed these mice and wild type controls to ischemia/reperfusion injury (IRI). The initial tubular injury at 24 hours post-IRI appeared to be unaffected, with the only observed difference being a decrease in inflammatory cytokine expression in the hypomorphs. However, we noted significant improvement in serum creatinine in the hypomorphs at 3 and 10 days after injury, and renal fibrosis was dramatically attenuated at the late timepoint. Assessment of Nrf2-regulated targets (GSTM1, GSTP1, NQO1) revealed higher expression in the hypomorphs at baseline. While injury tended to suppress these genes in wild-type mice, the suppression was attenuated or reversed in Keap1 hypomorphs, suggesting that protection in these mice was mediated by increased Nrf2 transcriptional activity. To assess the generalizability of our findings, we subjected the hypomorphs to unilateral ureteral obstruction (UUO) and again found significant protection and increased expression of Nrf2 targets. Overall, these results support the conclusion that the Nrf2 pathway is protective in a variety of kidney diseases.

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“…Similarly, the treatment of mice with bardoxolone methyl resulted in an ~1.3-fold increase in NQO1 protein level [23]. Treatment of 5/6 nephrectomy rats with dh404 resulted in an ~3.3-fold increase in NQO1 protein in the colon [5].…”

Section: Discussionmentioning

confidence: 99%

Expression of the NRF2 Target Gene NQO1 Is Enhanced in Mononuclear Cells in Human Chronic Kidney Disease

Shen

Rasmussen

Dong

et al. 2017

Oxidative Medicine and Cellular Longevity

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Reduced nuclear factor erythroid 2-related factor 2 (NRF2) pathway activity was reported in models of chronic kidney disease (CKD). Pharmacological activation of NRF2 is supposed to improve renal function, but data concerning the NRF2 activity in human CKD are lacking. We investigated the NRF2 target NAD(P)H:quinone oxidoreductase 1 (NQO1) as a readout parameter for NRF2 activity in monocytes of CKD patients (n = 63) compared to those of healthy controls (n = 16). The NQO1 gene expression was quantified using real-time PCR and the protein content by in-cell Western assays. We found a 3-4-fold increase in NQO1 gene expression in CKD 1–5 (n = 29; 3.5 for NQO1/ribosomal protein L41; p < 0.001). This was accompanied by a 1.1-fold increase in NQO1 protein (p = 0.06). Cardiovascular disease prevalence was higher in CKD 1–5 patients with higher compared to those with lower NQO1 gene expression (p = 0.02). In advanced uremia, in dialysis patients (n = 34), NQO1 gene expression was less robustly upregulated than that in CKD 1–5, while NQO1 protein was not upregulated. We conclude that in mononuclear cells of CKD patients, the NRF2 pathway is activated by coexisting pathogenic mechanisms, but in advanced uremia, the effectiveness of this upregulation is reduced. Both processes could interfere with pharmacological NRF2 activation.

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Integrated transcriptomic and proteomic analyses uncover regulatory roles of Nrf2 in the kidney

Cited by 46 publications

References 48 publications

Downregulation of Glutathione Biosynthesis Contributes to Oxidative Stress and Liver Dysfunction in Acute Kidney Injury

Downregulation of Glutathione Biosynthesis Contributes to Oxidative Stress and Liver Dysfunction in Acute Kidney Injury

Keap1 hypomorphism protects against ischemic and obstructive kidney disease

Expression of the NRF2 Target Gene NQO1 Is Enhanced in Mononuclear Cells in Human Chronic Kidney Disease

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