Nrf2 Protein Serum Concentration in Human CKD Shows a Biphasic Behavior

Rasmussen, Marianne Uggen; Hansen, Kristian Horsman; Scholze, Alexandra

doi:10.3390/antiox12040932

Cited by 7 publications

(7 citation statements)

References 41 publications

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“…Autophagia is important for the clearance of damaged proteins and organelles, and thus the prevention of inflammation ( 106 ). Inflammation has been proposed as being a prominent feature of CKD ( 45 , 108 , 109 ). Treatment with SGLT2 inhibitors may contribute to increased autophagia, decreased inflammation and thereby prevent fibrosis through their actions regarding ketone bodies.…”

Section: Resultsmentioning

confidence: 99%

Narrative review investigating the nephroprotective mechanisms of sodium glucose cotransporter type 2 inhibitors in diabetic and nondiabetic patients with chronic kidney disease

Speedtsberg,

Tepel

2023

Front. Endocrinol.

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Background and aimsOutcome trials using sodium glucose cotransporter type 2 inhibitors have consistently shown their potential to preserve kidney function in diabetic and nondiabetic patients. Several mechanisms have been introduced which may explain the nephroprotective effect of sodium glucose cotransporter type 2 inhibitors beyond lowering blood glucose. This current narrative review has the objective to describe main underlying mechanisms causing a nephroprotective effect and to show similarities as well as differences between proposed mechanisms which can be observed in patients with diabetic and nondiabetic chronic kidney disease.MethodsWe performed a narrative review of the literature on Pubmed and Embase. The research string comprised various combinations of items including “chronic kidney disease”, “sodium glucose cotransporter 2 inhibitor” and “mechanisms”. We searched for original research and review articles published until march, 2022. The databases were searched independently and the agreements by two authors were jointly obtained.ResultsSodium glucose cotransporter type 2 inhibitors show systemic, hemodynamic, and metabolic effects. Systemic effects include reduction of blood pressure without compensatory activation of the sympathetic nervous system. Hemodynamic effects include restoration of tubuloglomerular feedback which may improve pathologic hyperfiltration observed in most cases with chronic kidney disease. Current literature indicates that SGLT2i may not improve cortical oxygenation and may reduce medullar oxygenation.ConclusionSodium glucose cotransporter type 2 inhibitors cause nephroprotective effects by several mechanisms. However, several mediators which are involved in the underlying pathophysiology may be different between diabetic and nondiabetic patients.

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Section: Resultsmentioning

confidence: 99%

Narrative review investigating the nephroprotective mechanisms of sodium glucose cotransporter type 2 inhibitors in diabetic and nondiabetic patients with chronic kidney disease

Speedtsberg,

Tepel

2023

Front. Endocrinol.

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“…Robust activation of NRF2 is observed in the earlier stages of CKD development along with inflammation. In contrast, advanced CKD has been associated with the repression of the NRF2 pathway [ 101 ]. A patient-based study conducted by Rasmussen et al reported a biphasic pattern of NRF2 concentration in CKD wherein low glomerular filtration rates were associated with lower NRF2 protein concentration [ 101 ].…”

Section: Mitochondrial Function In Normal Renal Metabolismmentioning

confidence: 99%

“…In contrast, advanced CKD has been associated with the repression of the NRF2 pathway [ 101 ]. A patient-based study conducted by Rasmussen et al reported a biphasic pattern of NRF2 concentration in CKD wherein low glomerular filtration rates were associated with lower NRF2 protein concentration [ 101 ]. The study reported increased NRF2 protein levels in mild to moderate kidney function impairment, and the downregulation of NRF2 was observed in severe renal impairment [ 101 ].…”

Section: Mitochondrial Function In Normal Renal Metabolismmentioning

confidence: 99%

Mitochondrial Oxidative Metabolism: An Emerging Therapeutic Target to Improve CKD Outcomes

Mapuskar,

Vasquez-Martinez,

Mayoral-Andrade

et al. 2023

Biomedicines

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Chronic kidney disease (CKD) predisposes one toward end-stage renal disease (ESRD) and its associated morbidity and mortality. Significant metabolic perturbations in conjunction with alterations in redox status during CKD may induce increased production of reactive oxygen species (ROS), including superoxide (O2−) and hydrogen peroxide (H2O2). Increased O2− and H2O2 may contribute to the overall progression of renal injury as well as catalyze the onset of comorbidities. In this review, we discuss the role of mitochondrial oxidative metabolism in the pathology of CKD and the recent developments in treating CKD progression specifically targeted to the mitochondria. Recently published results from a Phase 2b clinical trial by our group as well as recently released data from a ROMAN: Phase 3 trial (NCT03689712) suggest avasopasem manganese (AVA) may protect kidneys from cisplatin-induced CKD. Several antioxidants are under investigation to protect normal tissues from cancer-therapy-associated injury. Although many of these antioxidants demonstrate efficacy in pre-clinical models, clinically relevant novel compounds that reduce the severity of AKI and delay the progression to CKD are needed to reduce the burden of kidney disease. In this review, we focus on the various metabolic pathways in the kidney, discuss the role of mitochondrial metabolism in kidney disease, and the general involvement of mitochondrial oxidative metabolism in CKD progression. Furthermore, we present up-to-date literature on utilizing targets of mitochondrial metabolism to delay the pathology of CKD in pre-clinical and clinical models. Finally, we discuss the current clinical trials that target the mitochondria that could potentially be instrumental in advancing the clinical exploration and prevention of CKD.

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“…Furthermore, Nrf2 inducers have been shown to have anti-inflammatory, antioxidant, and protective effects against renal injury in LN mice ( 4 ). Currently, clinical studies on Nrf2 have focused on advanced kidney disease, with reports indicating that Nrf2 expression correlated with the degree of renal failure and comorbidities ( 8 , 9 ) and Nrf2 expression varied among different types of immune cells and tissues ( 4 ). Meanwhile, regarding clinical trials, it was noted that the Nrf2 activator bardoxolone methyl did not reduce the risk of death due to ESRD in patients with type 2 diabetes and stage 4 chronic kidney disease.…”

Section: Introductionmentioning

confidence: 99%

“…It led to a higher rate of cardiovascular events compared to the placebo group, leading to the termination of the trial ( 10 ), as this Nrf2 activator resulted in an increased albuminuria ( 10 , 11 ). This necessitates the exploration of a uniform assay for Nrf2 protein levels and clinical evaluation of targeted Nrf2 therapy for renal disease ( 9 ). This makes it challenging to assess Nrf2 levels and administer interventions targeting Nrf2 in human LN cases.…”

Section: Introductionmentioning

confidence: 99%

Association of serum Nrf2 protein levels with disease activity and renal impairment in lupus nephritis

Li,

Guo,

Wei

et al. 2024

Front. Immunol.

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IntroductionWe aimed to investigate the relationship between nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression levels, lupus nephritis (LN) disease activity, and the degree of renal injury (based on the estimated glomerular filtration rate [eGFR]) in patients with LN.MethodsWe selected 40 healthy control participants and 102 patients with LN who were treated in the Second Hospital of Jilin University, China, for inclusion in this study. Patients with LN were classified into LN with high-eGFR and LN with low-eGFR groups. Nrf2 protein levels were measured in the serum and renal tissues of the participants in both groups to assess the correlation between Nrf2 protein levels and different LN disease states.ResultsThere was a significantly positive correlation between serum Nrf2 protein levels, the degree of renal injury, and systemic lupus erythematosus disease activity index (SLEDAI) scores in patients with LN. Nrf2 protein levels were higher in the LN with high-eGFR group than in the healthy control and LN with low-eGFR groups. In follow-up patients in the LN high eGFR group, Nrf2 protein levels decreased significantly after remission of disease activity.ConclusionNrf2 protein expression has a dual role in patients with LN. Nrf2 protein levels not only correlate with disease activity in patients with LN, but also with the degree of kidney injury. Before implementing targeted therapy for Nrf2, evaluating both Nrf2 protein expression and the disease state in patients with LN is necessary to better identify and place each patient in an appropriate patient group.

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Nrf2 Protein Serum Concentration in Human CKD Shows a Biphasic Behavior

Cited by 7 publications

References 41 publications

Narrative review investigating the nephroprotective mechanisms of sodium glucose cotransporter type 2 inhibitors in diabetic and nondiabetic patients with chronic kidney disease

Narrative review investigating the nephroprotective mechanisms of sodium glucose cotransporter type 2 inhibitors in diabetic and nondiabetic patients with chronic kidney disease

Mitochondrial Oxidative Metabolism: An Emerging Therapeutic Target to Improve CKD Outcomes

Association of serum Nrf2 protein levels with disease activity and renal impairment in lupus nephritis

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