Potent efficacy of Stachybotrys microspora triprenyl phenol-7, a small molecule having anti-inflammatory and antioxidant activities, in a mouse model of acute kidney injury

Pathophysiologically, the classification of acute kidney injury (AKI) can be divided into three categories: (1) prerenal, (2) intrinsic, and (3) postrenal. Emerging evidence supports the involvement of renal tubular epithelial cells and the innate and adaptive arms of the immune system in the pathogenesis of intrinsic AKI. Pro-inflammatory damage-associated molecular patterns, pathogen-associated molecular patterns, hypoxia inducible factors, toll-like receptors, complement system, oxidative stress, adhesion molecules, cell death, resident renal dendritic cells, neutrophils, T and B lymphocytes, macrophages, natural killer T cells, cytokines, and secreted chemokines contribute to the immunopathogenesis of AKI. However, other immune cells and pathways such as M2 macrophages, regulatory T cells, progranulin, and autophagy exhibit anti-inflammatory properties and facilitate kidney tissue repair after AKI. Thus, therapies for AKI include agents such as anti-inflammatory (e.g., recombinant alkaline phosphatase), antioxidants (iron chelators), and apoptosis inhibitors. In preclinical toxicity studies, drug-induced kidney injury can be seen after exposure to a nephrotoxicant test article due to immune mechanisms and dysregulation of innate, and/or adaptive cellular immunity. The focus of this review will be on intrinsic AKI, as it relates to the immune and renal systems cross talks focusing on the cellular and pathophysiologic mechanisms of AKI.

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Untargeted Metabolomics Reveals the Protective Effect of a Traditional Chinese Herbal Decoction on Cisplatin-Induced Acute Kidney Injury

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/8524132 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Yuyan Li ◽

Xinhui Liu ◽

Siqi Liu ◽

Jiandong Lu ◽

Jianping Chen ◽

...

Keyword(s):

Acute Kidney Injury ◽

Mouse Model ◽

High Performance ◽

Kidney Injury ◽

Underlying Mechanism ◽

Lysine Biosynthesis ◽

Chinese Herbal ◽

Flight Mass Spectrometry ◽

Herbal Decoction ◽

Group A

Our previous studies have demonstrated that Jian-Pi-Yi-Shen formula (JPYSF), a traditional Chinese herbal decoction, has a renoprotective effect in 5/6 nephrectomy-induced chronic kidney injury. However, the role and potential mechanisms of JPYSF in the treatment of acute kidney injury (AKI) remain unknown. This study was designed to test the beneficial effect of JPYSF in an AKI mouse model and to investigate the underlying mechanism by using metabolomics analysis. The AKI mouse model was induced by a single intraperitoneal injection of cisplatin at a dose of 20 mg/kg. The mice in the treatment group were pretreated orally with JPYSF (18.35 g/kg/d) for 5 days before cisplatin injection. Seventy-two hours after cisplatin injection, serum and kidney samples were collected for biochemical and histological examination. Ultra-high-performance liquid chromatography coupled with quadrupole time-of-ﬂight mass spectrometry (UHPLC-QTOF/MS) was applied to analyze metabolic profiling variations in the kidney. The results showed that pretreatment with JPYSF obviously reduced the levels of serum creatinine and blood urea nitrogen and alleviated renal pathological injury in AKI mice. Orthogonal partial least-squares discriminant analysis (OPLS-DA) score plot revealed a clear separation between the AKI and AKI + JPYSF group. A total of 68 and 87 significantly differentially expressed metabolites were identified in the kidney of AKI mice responding to JPYSF treatment in negative and positive ion mode, respectively. The pivotal pathways affected by JPYSF included vitamin B6 metabolism, alanine, aspartate and glutamate metabolism, lysine biosynthesis, and butanoate metabolism. In conclusion, JPYSF can protect the kidney from cisplatin-induced AKI, which may be associated with regulating renal metabolic disorders.

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SP158BCL3: AN NF-κB REGULATOR INDUCIBLE BY TWEAK IN ACUTE KIDNEY INJURY WITH ANTI-INFLAMMATORY AND ANTI-APOPTOTIC PROPERTIES IN TUBULAR CELLS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfx142.sp158 ◽

2017 ◽

Vol 32 (suppl_3) ◽

pp. iii157-iii157

Author(s):

Jonay Poveda ◽

Ana B Sanz ◽

Susana Carrasco ◽

Marta Ruiz-Ortega ◽

Pablo Cannata-Ortiz ◽

...

Keyword(s):

Acute Kidney Injury ◽

Kidney Injury ◽

Tubular Cells ◽

Anti Inflammatory

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P0511ENHANCER AND SUPER-ENHANCER DYNAMICS IN REPAIR AFTER ISCHEMIC ACUTE KIDNEY INJURY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa143.p0511 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Julia Wilflingseder ◽

Michaela Willi ◽

Hye Kyung Lee ◽

Hannes Olauson ◽

Jakub Jankowsky ◽

...

Keyword(s):

Acute Kidney Injury ◽

Transcription Factors ◽

Small Molecule ◽

Ischemia Reperfusion Injury ◽

Specific Binding ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Kidney Cortex ◽

Super Enhancer

Abstract Background and Aims The endogenous repair process of the mammalian kidney allows rapid recovery after acute kidney injury (AKI) through robust proliferation of tubular epithelial cells. There is currently limited understanding of which transcriptional regulators activate these repair programs and how transcriptional dysregulation leads to maladaptive repair. Here we investigate the existence of enhancer dynamics in the regenerating mouse kidney. Method RNA-seq and ChIP-seq (H3K27ac, H3K4m3, BRD4, POL2 and selected transcription factors) were performed on samples from repairing kidney cortex 2 days after ischemia/reperfusion injury (IRI) to identify activated genes, transcription factors, enhancer and super-enhancers associated with kidney repair. Further we investigated the role of super-enhancer activation in kidney repair through pharmacological BET inhibition using the small molecule JQ1 in vitro and in acute kidney injury models in vivo. Results Response to kidney injury leads to genome-wide alteration in enhancer repertoire in-vivo. We identified 16,781 enhancer sites (H3K27ac and BRD4 positive, H3K4me3 negative binding) active in SHAM and IRI samples; 6,512 lost and 9,774 gained after IRI. The lost and gained enhancer sites can be annotated to 62% and 63% of down- and up-regulated transcripts at day 2 after kidney injury, respectively. Super-enhancer analysis revealed 164 lost and 216 gained super-enhancer sites at IRI day 2. 385 super-enhancers maintain activity before and after injury. ChIP-seq profiles of selected transcription factors based on motif analysis show specific binding at corresponding enhancer sites. We observed lost enhancer binding of HNF4A and GR mainly at kidney related enhancer elements. In contrast, STAT3 showed increased binding at injury induces enhancer elements. No dynamic was observed for STAT5. Both transcription factor groups show corresponding mRNA changes after injury. Pharmacological inhibition of enhancer and super-enhancer activity by BRD4 inhibition (JQ1: 50mg/kg/day) before IRI leads to suppression of 40% of injury-induced transcripts associated with cell cycle regulation and significantly increased mortality between days 2 and 3 after AKI. Conclusion This is the first demonstration of enhancer and super-enhancer function in the repairing kidney. In addition, our data call attention to potential caveats for use of small molecule inhibitors of BET proteins that are currently being tested in clinical trials in cancer patients who are at risk for AKI. Our analyses of enhancer dynamics after kidney injury in vivo have the potential to identify new targets for therapeutic intervention.

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Antioxidative, Antiapoptotic, and Anti-Inflammatory Effects of Apamin in a Murine Model of Lipopolysaccharide-Induced Acute Kidney Injury

Molecules ◽

10.3390/molecules25235717 ◽

2020 ◽

Vol 25 (23) ◽

pp. 5717 ◽

Cited By ~ 1

Author(s):

Jung-Yeon Kim ◽

Jaechan Leem ◽

Kwan-Kyu Park

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Immune Cell ◽

Inflammatory Responses ◽

Tissue Injury ◽

Therapeutic Option ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Kidney Injury ◽

Heme Oxygenase 1 ◽

Anti Inflammatory

Sepsis is the major cause of acute kidney injury (AKI) in severely ill patients, but only limited therapeutic options are available. During sepsis, lipopolysaccharide (LPS), an endotoxin derived from bacteria, activates signaling cascades involved in inflammatory responses and tissue injury. Apamin is a component of bee venom and has been shown to exert antioxidative, antiapoptotic, and anti-inflammatory activities. However, the effect of apamin on LPS-induced AKI has not been elucidated. Here, we show that apamin treatment significantly ameliorated renal dysfunction and histological injury, especially tubular injury, in LPS-injected mice. Apamin also suppressed LPS-induced oxidative stress through modulating the expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and heme oxygenase-1. Moreover, tubular cell apoptosis with caspase-3 activation in LPS-injected mice was significantly attenuated by apamin. Apamin also inhibited cytokine production and immune cell accumulation, suppressed toll-like receptor 4 pathway, and downregulated vascular adhesion molecules. Taken together, these results suggest that apamin ameliorates LPS-induced renal injury through inhibiting oxidative stress, apoptosis of tubular epithelial cells, and inflammation. Apamin might be a potential therapeutic option for septic AKI.

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