Advanced Oxidation Protein Products Contribute to Renal Tubulopathy via Perturbation of Renal Fatty Acids

Imafuku, Tadashi; Watanabe, Hiroshi; Satoh, Takao; Matsuzaka, Takashi; Inazumi, Tomoaki; Kato, Hiromasa; Tanaka, Sonosuke; Nakamura, Yuka; Nakano, Tsutomu; Tokumaru, Kai; Maeda, Hitoshi; Mukunoki, Ayumi; Tanaka, Takeo; Nakagata, Naomi; Tanaka, Motoko; Matsushita, Kazutaka; Tsuchiya, Soken; Sugimoto, Yukihiko; Shimano, Hitoshi; Fukagawa, Masafumi; Maruyama, Toru

doi:10.34067/kid.0000772019

Cited by 8 publications

(7 citation statements)

References 51 publications

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“…In the kidneys, skewing of fatty acid metabolism in tubular epithelial cells toward fatty acid synthesis is both an outcome and a mediator of kidney oxidative stress, injury, and fibrosis. 22,33,34 Further studies quantifying a broader set of lipid metabolism pathway transcripts in high-quality RNA samples from individuals with CA TCMR are necessary. In addition to small cohort size, this study is limited by highly targeted transcriptional profiling and lack of cross-platform validation.…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, the transcript most significantly correlated with eGFR decline is ELOVL6 (r ¼ -0.55; P ¼ 0.004), encoding a long-chain fatty acid elongase, which is induced by advanced oxidation protein products and contributes to both tubular injury and kidney fibrosis. 22 Fatty acid synthesis has been previously shown to promote fibrosis, 23 and by enrichment analysis using gene ontology tools, among the targets negatively correlated with DeGFR, there is a significant enrichment for transcripts involved in matrix deposition, epithelial dedifferentiation, and myofibroblast activation (Supplementary Table S3). These include a number of transforming growth factor-b signaling pathway effectors (LOXL1, THBS2, DDR2, FGF2, and FAP), as well as NOTCH3 and EGFR.…”

Section: In Allografts With Ca Tcmr Transcripts With Opposing Functions In Fatty Acid Metabolism Correlate With Treatment Responsementioning

confidence: 99%

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Chronic active T cell–mediated rejection is variably responsive to immunosuppressive therapy

Kung

Sandhu

Haas

et al. 2021

Kidney International

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Chronic active T cell-mediated rejection (CA TCMR) is a newly described variant of kidney allograft rejection associated with long-term graft loss. Whether this form of rejection is related to under immunosuppression is debated and the benefit of immunosuppressive therapy in CA TCMR is unknown. Here we investigate the amenability of CA TCMR to treatment and examine the impact of clinical, histologic, and molecular parameters on outcomes. In a retrospective single institution review, we identified 48 cases of isolated CA TCMR, of which 44 were treated with pulse steroids or anti-thymocyte globulin, or both. Defining treatment response as an at least 50% estimated glomerular filtration rate recovery, a response was achieved in 20% of cases at four weeks post initiation of immunosuppressive therapy. Treatment responsiveness did not reflect the presence of concomitant acute T cellmediated rejection, and was not significantly different between cases with mild, moderate, and severe parenchymal scarring. Although not statistically significant, there was a trend toward greater treatment responsiveness in cases with moderate as opposed to severe tubulitis. By targeted transcriptional profiling, increased allograft mast cells and alterations in lipid metabolism were identified as possible features of treatment resistant CA TCMR. Thus, our study shows that although its prognosis is generally poor, CA TCMR is not a homogenous entity and in a subset of cases, improvement in kidney function can be achieved with immunosuppressive therapy.

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Section: Discussionmentioning

confidence: 99%

Section: In Allografts With Ca Tcmr Transcripts With Opposing Functions In Fatty Acid Metabolism Correlate With Treatment Responsementioning

confidence: 99%

Chronic active T cell–mediated rejection is variably responsive to immunosuppressive therapy

Kung

Sandhu

Haas

et al. 2021

Kidney International

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“…Advanced oxidation protein products were prepared as described in a previous study 15 . HSA was defatted by treatment with activated carbon 15 .…”

Section: Methodsmentioning

confidence: 99%

“…Advanced oxidation protein products were prepared as described in a previous study 15 . HSA was defatted by treatment with activated carbon 15 . Defatted HSA (300 μM) was incubated with 100 mM chloramine T in 67 mM phosphate buffer (pH 8.0) for 1 h at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Advanced oxidation protein products contribute to chronic kidney disease‐induced muscle atrophy by inducing oxidative stress via CD36/NADPH oxidase pathway

Kato

Watanabe

Imafuku

et al. 2021

J cachexia sarcopenia muscle

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Background Sarcopenia with chronic kidney disease (CKD) progression is associated with life prognosis. Oxidative stress has attracted interest as a trigger for causing CKD‐related muscular atrophy. Advanced oxidation protein products (AOPPs), a uraemic toxin, are known to increase oxidative stress. However, the role of AOPPs on CKD‐induced muscle atrophy remains unclear. Methods In a retrospective case–control clinical study, we evaluated the relationship between serum AOPPs levels and muscle strength in haemodialysis patients with sarcopenia (n = 26, mean age ± SEM: 78.5 ± 1.4 years for male patients; n = 22, mean age ± SEM: 79.1 ± 1.5 for female patients), pre‐sarcopenia (n = 12, mean age ± SEM: 73.8 ± 2.0 years for male patients; n = 4, mean age ± SEM: 74.3 ± 4.1 for female patients) or without sarcopenia (n = 12, mean age ± SEM: 71.3 ± 1.6 years for male patients; n = 7, mean age ± SEM: 77.7 ± 1.6 for female ). The molecular mechanism responsible for the AOPPs‐induced muscle atrophy was investigated by using 5/6‐nephrectomized CKD mice, AOPPs‐overloaded mice, and C2C12 mouse myoblast cells. Results The haemodialysis patients with sarcopenia showed higher serum AOPPs levels as compared with the patients without sarcopenia. The serum AOPPs levels showed a negative correlation with grip strength (P < 0.01 for male patients, P < 0.01 for female patients) and skeletal muscle index (P < 0.01 for male patients). Serum AOPPs levels showed a positive correlation with cysteinylated albumin (Cys‐albumin), a marker of oxidative stress (r2 = 0.398, P < 0.01). In the gastrocnemius of CKD mice, muscle AOPPs levels were also increased, and it showed a positive correlation with atrogin‐1 (r2 = 0.538, P < 0.01) and myostatin expression (r2 = 0.421, P < 0.05), but a negative correlation with PGC‐1α expression (r2 = 0.405, P < 0.05). Using C2C12 cells, AOPPs increased atrogin‐1 and myostatin expression through the production of reactive oxygen species via CD36/NADPH oxidase pathway, and decreased myotube formation. AOPPs also induced mitochondrial dysfunction. In the AOPPs‐overloaded mice showed that decreasing running time and hanging time accompanied by increasing AOPPs levels and decreasing cross‐sectional area in gastrocnemius. Conclusions Advanced oxidation protein products contribute to CKD‐induced sarcopenia, suggesting that AOPPs or its downstream signalling pathway could be a therapeutic target for the treatment of CKD‐induced sarcopenia. Serum AOPPs or Cys‐albumin levels could be a new diagnostic marker for sarcopenia in CKD.

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“…We recently clarified that AOPPs are involved in the development of renal tubular disorders by inducing abnormal fatty acid metabolism in renal tubular cells. 36) Regarding the muscle atrophy and muscle weakness (sarcopenia) observed in CKD, AOPPs were found to show skeletal muscle atrophy and mitochondrial dysfunction effects. 37) Interestingly, we also found that serum AOPPs and oxidized albumin levels were higher in dialysis patients with sarcopenia than in non-sarcopenia patients, suggesting that AOPPs and oxidized albumin may be applicable for use as diagnostic markers for sarcopenia in CKD patients.…”

Section: Oxidized Albumin As a Renal Exacer-bating Factormentioning

confidence: 99%

Oxidized Albumin: Evaluation of Oxidative Stress as a Marker for the Progression of Kidney Disease

Watanabe

2022

Biological & Pharmaceutical Bulletin

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Oxidative stress has been reported to be associated with the progression of renal pathology as well as with the onset of complications associated with this condition. Bardoxolone methyl, a nuclear factorerythroid 2-related factor 2 (Nrf2) activator with anti-oxidative and inflammatory modulation effects, has been reported to improve renal function in clinical trials. As of this writing, there have been no systems for the quantitative evaluation of oxidative stress that could be applied as a clinical test. We recently reported on post-translational modifications of albumin using electrospray-ionization time-of-flight mass spectrometry (ESI-TOF MS) and the results indicated that oxidized albumin (cysteinylated albumin: a molecule that was oxidatively cysteinylated at Cys34) was found to increase with the progression of renal pathology. A clinical study demonstrated that monitoring the levels of oxidized albumin could be useful for the early diagnosis of diabetic kidney disease and for predicting renal prognosis. Higher levels of serum oxidized albumin were also associated with cardiovascular complications or sarcopenia in patients who were undergoing hemodialysis. The overall findings indicate that oxidized albumin could also be an index of therapeutic efficacy against kidney disease. Oxidized albumin is not only a marker for kidney disease but also a nephrotoxic substance. This suggests that measuring the levels of oxidized albumin could be a biomarker for diagnosing the progression of and complications associated with renal disease in addition to evaluating the efficacy of therapeutic drugs.

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Advanced Oxidation Protein Products Contribute to Renal Tubulopathy via Perturbation of Renal Fatty Acids

Cited by 8 publications

References 51 publications

Chronic active T cell–mediated rejection is variably responsive to immunosuppressive therapy

Chronic active T cell–mediated rejection is variably responsive to immunosuppressive therapy

Advanced oxidation protein products contribute to chronic kidney disease‐induced muscle atrophy by inducing oxidative stress via CD36/NADPH oxidase pathway

Oxidized Albumin: Evaluation of Oxidative Stress as a Marker for the Progression of Kidney Disease

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