Metabolomics analysis reveals the association between lipid abnormalities and oxidative stress, inflammation, fibrosis and Nrf2 dysfunction in aristolochic acid-induced nephropathy

Zhao, Ying-Yong; Wang, Huiling; Cheng, Xian‐Long; Wei, Feng; Xu, Bo; Lin, Rui‐Chao; Vaziri, Nosratola D.

doi:10.1038/srep12936

Cited by 149 publications

(85 citation statements)

References 29 publications

(39 reference statements)

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“…We found that, compared to the contralateral uninjured kidneys, injured kidneys slightly induce the expression of NRF2 target genes within 24 h after injury and accumulate ROS and electrophiles. This induction is transient, and the levels fall below baseline levels the day after injury (day 1), in agreement with previous reports that have utilized different animal models of nephropathy [61,62]. The tubules then undergo damage from oxidative stress caused by oxidative DNA adducts, including 8-hydroxydeoxyguanosine.…”

Section: Evidence For the Beneficial Effects Of Nrf2 Activation In Thsupporting

confidence: 76%

Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression

Nezu¹,

Suzuki

Yamamoto³

2017

Am J Nephrol

2,544

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Background: Nuclear factor erythroid 2-related factor 2 (NRF2) is a critical transcription factor for the antioxidative stress response and it activates a variety of cytoprotective genes related to redox and detoxification. NRF2 activity is regulated by the oxidative-stress sensor molecule Kelch-like ECH-associated protein 1 (KEAP1) that induces proteasomal degradation of NRF2 through ubiquitinating NRF2 under unstressed conditions. Because oxidative stress is a major pathogenic and aggravating factor for kidney diseases, the KEAP1-NRF2 system has been proposed to be a therapeutic target for renal protection. Summary: Oxidative-stress molecules, such as reactive oxygen species, accumulate in the kidneys of animal models for acute kidney injury (AKI), in which NRF2 is transiently and slightly activated. Genetic or pharmacological enhancement of NRF2 activity in the renal tubules significantly ameliorates damage related to AKI and prevents AKI progression to chronic kidney disease (CKD) by reducing oxidative stress. These beneficial effects of NRF2 activation highlight the KEAP1-NRF2 system as an important target for kidney disease treatment. However, a phase-3 clinical trial of a KEAP1 inhibitor for patients with stage 4 CKD and type-2 diabetes mellitus (T2DM) was terminated due to the occurrence of cardiovascular events. Because recent basic studies have accumulated positive effects of KEAP1 inhibitors in moderate stages of CKD, phase-2 trials have been restarted. The data from the ongoing projects demonstrate that a KEAP1 inhibitor improves the glomerular filtration rate in patients with stage 3 CKD and T2DM without safety concerns. Key Message: The KEAP1-NRF2 system is one of the most promising therapeutic targets for kidney disease, and KEAP1 inhibitors could be part of critical therapies for kidney disease.

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Section: Evidence For the Beneficial Effects Of Nrf2 Activation In Thsupporting

confidence: 76%

Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression

Nezu¹,

Suzuki

Yamamoto³

2017

Am J Nephrol

2,544

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“…Another study demonstrated the association of altered plasma valine, alanine, glutamate and glycine with different stages of CKD [32]. Additionally, urine asparagine, leucine, proline and citrulline were significant increased in advanced CKD patients [3], [34]. The present study identified 5-HTP, homocystine and leucine as plasma biomarker candidates.…”

Section: Discussionsupporting

confidence: 59%

“…Moreover, the underlying causes of chronic kidney disease (CKD) such as diabetes and autoimmune disorders independently impact generation of metabolites and compound the effects of kidney disease. Technological advances which allow comprehensive determination of small molecular weight metabolites have provided an important tool to measure the full spectrum of endogenous metabolites in biological samples [1], [2], [3]. Application of these sophisticated systems has provided a valuable tool for early diagnosis, identification of reliable biomarkers, elucidation of the mechanism of various diseases, and monitoring of their progression and response to therapeutic interventions.…”

Section: Introductionmentioning

confidence: 99%

Gene and protein expressions and metabolomics exhibit activated redox signaling and wnt/β-catenin pathway are associated with metabolite dysfunction in patients with chronic kidney disease

et al. 2017

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Changes in plasma concentration of small organic metabolites could be due to their altered production or urinary excretion and changes in their urine concentration may be due to the changes in their filtered load, tubular reabsorption, and/or altered urine volume. Therefore, these factors should be considered in interpretation of the changes observed in plasma or urine of the target metabolite(s). Fasting plasma and urine samples from 180 CKD patients and 120 age-matched healthy controls were determined by UPLC-HDMS-metabolomics and quantitative real-time RT-PCR techniques. Compared with healthy controls, patients with CKD showed activation of NF-κB and up-regulation of pro-inflammatory and pro-oxidant mRNA and protein expression as well as down-regulation of Nrf2-associated anti-oxidant gene mRNA and protein expression, accompanied by activated canonical Wnt/β-catenin signaling. 124 plasma and 128 urine metabolites were identified and 40 metabolites were significantly altered in both plasma and urine. Plasma concentration and urine excretion of 25 metabolites were distinctly different between CKD and controls. They were related to amino acid, methylamine, purine and lipid metabolisms. Logistic regression identified four plasma and five urine metabolites. Parts of them were good correlated with eGFR or serum creatinine. 5-Methoxytryptophan and homocystine and citrulline were good correlated with both eGFR and creatinine. Clinical factors were incorporated to establish predictive models. The enhanced metabolite model showed 5-methoxytryptophan, homocystine and citrulline have satisfactory accuracy, sensitivity and specificity for predictive CKD. The dysregulation of CKD was related to amino acid, methylamine, purine and lipid metabolisms. 5-methoxytryptophan, homocystine and citrulline could be considered as additional GFR-associated biomarker candidates and for indicating advanced renal injury. CKD caused dysregulation of the plasma and urine metabolome, activation of inflammatory/oxidative pathway and Wnt/β-catenin signaling and suppression of antioxidant pathway.

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“…In addition, uptake of filtered lipid-carrying proteins by the proximal tubules in patients and animal models with protein uria can lead to the accumulation of lipids in proximal tubular epithelial cells 6 . These events can contribute to CKD progression by promoting glomerulosclerosis and tubular damage and dysfunction 97,98 . By preventing and reversing oxidation of lipoproteins, as well as mediating the removal of the intracellular lipid stores, normal HDL can limit the accumulation of cellular lipids in the renal tissue as it does in the vascular wall.…”

Section: Progression Of Ckdmentioning

confidence: 99%

HDL abnormalities in nephrotic syndrome and chronic kidney disease

2015

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| Normal HDL activity confers cardiovascular and overall protection by mediating reverse cholesterol transport and through its potent anti-inflammatory, antioxidant, and antithrombotic functions. Serum lipid profile, as well as various aspects of HDL metabolism, structure, and function can be profoundly altered in patients with nephrotic range proteinuria or chronic kidney disease (CKD). These abnormalities can, in turn, contribute to the progression of cardiovascular complications and various other comorbidities, such as foam cell formation, atherosclerosis, and/or glomerulosclerosis, in affected patients. The presence and severity of proteinuria and renal insufficiency, as well as dietary and drug regimens, pre-existing genetic disorders of lipid metabolism, and renal replacement therapies (including haemodialysis, peritoneal dialysis, and renal transplantation) determine the natural history of lipid disorders in patients with kidney disease. Despite the adverse effects associated with dysregulated reverse cholesterol transport and advances in our understanding of the underlying mechanisms, safe and effective therapeutic interventions are currently lacking. This Review provides an overview of HDL metabolism under normal conditions, and discusses the features, mechanisms, and consequences of HDL abnormalities in patients with nephrotic syndrome or advanced CKD.

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Metabolomics analysis reveals the association between lipid abnormalities and oxidative stress, inflammation, fibrosis and Nrf2 dysfunction in aristolochic acid-induced nephropathy

Cited by 149 publications

References 29 publications

Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression

Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression

Gene and protein expressions and metabolomics exhibit activated redox signaling and wnt/β-catenin pathway are associated with metabolite dysfunction in patients with chronic kidney disease

HDL abnormalities in nephrotic syndrome and chronic kidney disease

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