Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis: mitochondria-targeted antioxidant mitigates injury

Patil, Naeem K.; Parajuli, Nirmala; MacMillan-Crow, Lee Ann; Mayeux, Philip R.

doi:10.1152/ajprenal.00643.2013

Cited by 159 publications

(169 citation statements)

References 64 publications

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“…31,32 Less is known, however, about the mechanisms underlying oliguria, despite it being a diagnostic criterion of AKI in several guidelines (e.g., AKIN, RIFLE, and KDIGO). [15][16][17] To our knowledge, this study is the first to show that (1) LPS signaling through a TLR4-dependent mechanism is associated with reduced intraproximal tubular urine flow rate and (2) the dilation of LPScontaining tubules in response to fluid resuscitation may distinguish urine flow rate responders and nonresponders during early phases of endotoxemia in mice.…”

Section: Discussionmentioning

confidence: 99%

Reduction of Tubular Flow Rate as a Mechanism of Oliguria in the Early Phase of Endotoxemia Revealed by Intravital Imaging

Nakano¹,

Doi

Kitamura

et al. 2015

Journal of the American Society of Nephrology

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Urine output is widely used as a criterion for the diagnosis of AKI. Although several potential mechanisms of septic AKI have been identified, regulation of urine flow after glomerular filtration has not been evaluated. This study evaluated changes in urine flow in mice with septic AKI. The intratubular urine flow rate was monitored in real time by intravital imaging using two-photon laser microscopy. The tubular flow rate, as measured by freely filtered dye (FITC-inulin or Lucifer yellow), time-dependently declined after LPS injection. At 2 hours, the tubular flow rate was slower in mice injected with LPS than in mice injected with saline, whereas BP and GFR were similar in the two groups. Importantly, fluorophore-conjugated LPS selectively accumulated in the proximal tubules that showed reduced tubular flow at 2 hours and luminal obstruction with cell swelling at 24 hours. Delipidation of LPS or deletion of Toll-like receptor 4 in mice abolished these effects, whereas neutralization of TNF-a had little effect on LPS-induced tubular flow retention. Rapid intravenous fluid resuscitation within 6 hours improved the tubular flow rate only when accompanied by the dilation of obstructed proximal tubules with accumulated LPS. These findings suggest that LPS reduces the intratubular urine flow rate during early phases of endotoxemia through a Toll-like receptor 4-dependent mechanism, and that the efficacy of fluid resuscitation may depend on the response of tubules with LPS accumulation.

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Section: Discussionmentioning

confidence: 99%

Reduction of Tubular Flow Rate as a Mechanism of Oliguria in the Early Phase of Endotoxemia Revealed by Intravital Imaging

Nakano¹,

Doi

Kitamura

et al. 2015

Journal of the American Society of Nephrology

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“…Kidney tissue, mouse 17,96 . Expression of mitochondrial protein after treatment of AKI by antioxidant 17 .…”

Section: Acute Kidney Injurymentioning

confidence: 99%

“…Expression of mitochondrial protein after treatment of AKI by antioxidant 17 . Protective mechanism of mitochondrial sirtuin 96 .…”

Section: Acute Kidney Injurymentioning

confidence: 99%

“…Although proteomic analysis of mitochondria or kidney tissue affected by AKI is not available to date, experimental data suggest that changes in mitochondrial proteins structure and activity could substantially contribute to the onset or progress of renal dysfunction associated with AKI (ref. 17 ). Recent research showed that mitochondrial proteins could be an important target for therapy 96,97 .…”

Section: Acute Kidney Injurymentioning

confidence: 99%

“…Specific impairment of renal mitochondrial metabolism has also been observed in cancer 13 , diabetes 14,15 and as a consequence of toxic metabolite removal 16 . Emerging evidence also suggests that mitochondria represent a promising target for novel treatments [17][18][19] . Proteomics was initially defined as an effort to identify and describe the complete set of proteins expressed in biological systems.…”

Section: Introductionmentioning

confidence: 99%

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Proteomic approaches to the study of renal mitochondria

Tůma¹,

Kuncová²,

Mareš³

et al. 2016

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background and Aims. Dysfunction of kidney mitochondria plays a critical role in the pathogenesis of a number of renal diseases. Proteomics represents an untargeted attempt to reveal the remodeling of mitochondrial proteins during disease. Combination of separation methods and mass spectrometry allows identification and quantitative analysis of mitochondrial proteins including protein complexes. The aim of this review is to summarize the methods and applications of proteomics to renal mitochondria. Methods. Using keywords "mitochondria", "kidney", "proteomics", scientific databases (PubMed and Web of knowledge) were searched from 2000 to August 2015 for articles describing methods and applications of proteomics to analysis of mitochondrial proteins in kidney. Included were publications on mitochondrial proteins in kidneys of humans and animal model in health and disease. Results and Conclusion. Proteomics of renal mitochondria has been/is mostly used in diabetes, hypertension, acidosis, nephrotoxicity and renal cancer. Integration of proteomics with other methods for examining protein activity is promising for insight into the role of renal mitochondria in pathological states. Several challenges were identified: selection of appropriate model organism, sensitivity of analytical methods and analysis of mitochondrial proteome in different renal zones/biopsies in the course of various kidney disorders.

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Histone H3K18 and Ezrin Lactylation Promote Renal Dysfunction in Sepsis‐Associated Acute Kidney Injury

Qiao,

Tan,

Liu

et al. 2024

Advanced Science

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Histone lactylation is a metabolic stress‐related histone modification. However, the role of histone lactylation in the development of sepsis‐associated acute kidney injury (SA‐AKI) remains unclear. Here, histone H3K18 lactylation (H3K18la) is elevated in SA‐AKI, which is reported in this study. Furthermore, this lactate‐dependent histone modification is enriched at the promoter of Ras homolog gene family member A (RhoA) and positively correlated with the transcription. Correction of abnormal lactate levels resulted in a reversal of abnormal histone lactylation at the promoter of RhoA. Examination of related mechanism revealed that histone lactylation promoted the RhoA/Rho‐associated protein kinase (ROCK) /Ezrin signaling, the activation of nuclear factor‐κB (NF‐κB), inflammation, cell apoptosis, and aggravated renal dysfunction. In addition, Ezrin can undergo lactylation modification. Multiple lactylation sites are identified in Ezrin and confirmed that lactylation mainly occurred at the K263 site. The role of histone lactylation is revealed in SA‐AKI and reportes a novel post‐translational modification in Ezrin. Its potential role in regulating inflammatory metabolic adaptation of renal proximal tubule epithelial cells is also elucidated. The results provide novel insights into the epigenetic regulation of the onset of SA‐AKI.

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Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis: mitochondria-targeted antioxidant mitigates injury

Cited by 159 publications

References 64 publications

Reduction of Tubular Flow Rate as a Mechanism of Oliguria in the Early Phase of Endotoxemia Revealed by Intravital Imaging

Reduction of Tubular Flow Rate as a Mechanism of Oliguria in the Early Phase of Endotoxemia Revealed by Intravital Imaging

Proteomic approaches to the study of renal mitochondria

Histone H3K18 and Ezrin Lactylation Promote Renal Dysfunction in Sepsis‐Associated Acute Kidney Injury

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