Systemic inflammation and oxidative stress in hemodialysis patients are associated with down-regulation of Nrf2

Pedruzzi, Liliana Magnago; Cardozo, Ludmila F M F; Daleprane, Julio Beltrame; Stockler‐Pinto, Milena Barcza; Monteiro, Elisa Bernardes; Leite, Maurilo; Vaziri, Nosratola D.; Mafra, Denise

doi:10.1007/s40620-014-0162-0

Cited by 81 publications

(68 citation statements)

References 41 publications

(45 reference statements)

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“…Similar findings with other known activators such as resveratrol support the therapeutic targeting of this system to ameliorate the oxidative damage and glucose-induced mesangial cell proliferation, inflammation, and fibrosis which underlies diabetic nephropathy [29, 3 0]. Lower levels of Nrf2 in the peripheral blood of patients with chronic DKD further support the contribution of an impaired Nrf2 antioxidant signaling pathway to systemic oxidative overload and inflammation in diabetic nephropathy [31]. Few studies have focused on podocytes, particularly podocyte mitochondrial function, and to the best of our knowledge, we are the first to report the protection provided by Nrf2-ARE pathway activation against mitochondrial dysfunction in podocytes induced by HG.…”

Section: Cellular Physiology and Biochemistrysupporting

confidence: 61%

Activation of the Nrf2-ARE Pathway Ameliorates Hyperglycemia-Mediated Mitochondrial Dysfunction in Podocytes Partly Through Sirt1

Zhang¹,

Deng²,

Zhang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Previously we have shown that activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-antioxidant response element (ARE) attenuated hyperglycemia-induced damage in podocytes, but the molecular mechanism remains unknown. Methods: Tert-butylhydroquinone (t-BHQ) and small interfering RNAs (siRNAs) were used to regulate Nrf2 expression, while nicotinamide and siRNAs were used to regulate sirtuin 1 (Sirt1) activity and expression, respectively. Mitochondrial superoxide, membrane potential and ATP levels were measured to assess changes in mitochondrial function. Nephrin and synaptopodin expression were measured by western blot analysis. Human podocytes and db/db diabetic mice were used in this study. Results: t-BHQ pretreatment of human podocytes exposed to high glucose (HG) alleviated mitochondrial dysfunction, enhanced the expression of Sirt1, nephrin and synaptopodin and lowered BSA permeability compared with podocytes exposed to HG without t-BHQ pretreatment (p< 0.05). Human podocytes exposed to HG had more severe mitochondrial dysfunction, lower expression of Sirt1, synaptopodin and nephrin and higher BSA permeability than podocytes exposed to HG when Nrf2 expression was downregulated by siRNAs (p< 0.05). The protection provided by activation of the Nrf-ARE pathway in podocytes exposed to HG was partially diminished when Sirt1 expression or activity was decreased by siRNAs or inhibitor compared with podocytes exposed to HG and pretreated with t-BHQ (p< 0.05). When nicotinamide and t-BHQ were both administered to db/db mice, we observed higher levels of urinary albumin/creatinine, lower nephrin and synaptopodin expression, more severe mesangial matrix deposition, collagen deposition on pathological slides and mitochondrial structural damage in podocytes compared to db/db mice treated only with t-BHQ. Conclusions: Our findings suggest that crosstalk between Sirt1 and the Nrf2-ARE anti-oxidative pathway forms a positive feedback loop and that protection provided by t-BHQ activation of the Nrf2-ARE pathway in db/db mice is partly dependent on Sirt1.

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Section: Cellular Physiology and Biochemistrysupporting

confidence: 61%

Activation of the Nrf2-ARE Pathway Ameliorates Hyperglycemia-Mediated Mitochondrial Dysfunction in Podocytes Partly Through Sirt1

Zhang¹,

Deng²,

Zhang³

et al. 2018

Cell Physiol Biochem

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“…In humans, microarray analysis in Tako-Tsubo cardiomyopathy indicated an increase in pathologic ROS levels and a compensatory upregulation of NRF2 during the acute phase of this contractile dysfunction (Nef et al, 2008). Recently, systemic inflammation and pathologic ROS formation in hemodialysis patients were associated with downregulation of NRF2 (Pedruzzi et al, 2015), and two promoter polymorphisms (rs35652124 and rs6721961) were associated with increased risk of mortality in these patients (Shimoyama et al, 2014).…”

Section: E Nuclear Factor (Erythroid-derived 2)-like 2 In the Cardiomentioning

confidence: 99%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

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“…Experimental studies in kidney cells and animal models, as well as limited data in humans, have implicated an increase in Nrf2 as beneficial in a range of kidney diseases including acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy (DN), polycystic kidney disease and hypertension (1, 2). The protective effects of Nrf2 regulated antioxidant responses are largely attributed to its transcriptional control over hundreds of antioxidant and xenobiotic genes that are actively transcribed following an insult.…”

Section: Commentarymentioning

confidence: 99%

Reviving the promise of transcription factor Nrf2-based therapeutics for kidney diseases

Noel

Hamad

Rabb

2015

Kidney International

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The transcription factor Nrf2 has been shown to play an important role in many different kidney diseases from AKI to CKD, and there have been preliminary Nrf2 based therapeutic trials in humans. In the current issue of Kidney Int, Shelton and colleagues present an integrated transcriptomic and proteomic analysis of mouse kidney to reveal Nrf2 targets with potentially important roles in kidney homeostasis and pathophysiology. These results can help further our understanding of Nrf2 based mechanisms and develop therapeutics for a wide range of kidney diseases.

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Systemic inflammation and oxidative stress in hemodialysis patients are associated with down-regulation of Nrf2

Cited by 81 publications

References 41 publications

Activation of the Nrf2-ARE Pathway Ameliorates Hyperglycemia-Mediated Mitochondrial Dysfunction in Podocytes Partly Through Sirt1

Activation of the Nrf2-ARE Pathway Ameliorates Hyperglycemia-Mediated Mitochondrial Dysfunction in Podocytes Partly Through Sirt1

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Reviving the promise of transcription factor Nrf2-based therapeutics for kidney diseases

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