Inhibition of histone deacetylation with vorinostat does not prevent tunicamycin-mediated acute kidney injury

Endoplasmic reticulum (ER) stress is associated with acute kidney injury (AKI) caused by various mechanisms, including antibiotics, non-steroidal anti-inflammatory drugs, cisplatin, and radiocontrast. Tunicamycin (TM) is a nucleoside antibiotic that induces ER stress and is a commonly used model of AKI. 4-phenylbutyrate (4-PBA) is a chemical chaperone and histone deacetylase (HDAC) inhibitor and has been shown to protect the kidney from ER stress, apoptosis, and structural damage in a tunicamycin model of AKI. The renal protection provided by 4-PBA is attributed to its ability to prevent misfolded protein aggregation and inhibit ER stress; however, the HDAC inhibitor effects of 4-PBA have not been examined in the TM-induced model of AKI. As such, the main objective of this study was to determine if histone hyperacetylation provides any protective effects against TM-mediated AKI. The FDA-approved HDAC inhibitor vorinostat was used, as it has no ER stress inhibitory effects and therefore the histone hyperacetylation properties alone could be investigated. In vitro work demonstrated that vorinostat inhibited histone deacetylation in cultured proximal tubular cells but did not prevent ER stress or protein aggregation induced by TM. Vorinostat induced a significant increase in cell death, and exacerbated TM-mediated total cell death and apoptotic cell death. Wild type male mice were treated with TM (0.5 mg/kg, intraperitoneal injection), with or without vorinostat (50 mg/kg/day) or 4-PBA (1 g/kg/day). Mice treated with 4-PBA or vorinostat exhibited similar levels of histone hyperacetylation. Expression of the pro-apoptotic protein CHOP was induced with TM, and not inhibited by vorinostat. Further, vorinostat did not prevent any renal damage or decline in renal function caused by tunicamycin. These data suggest that the protective mechanisms found by 4-PBA are primarily due to its molecular chaperone properties, and the HDAC inhibitors used did not provide any protection against renal injury caused by ER stress.

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Chemical chaperone, TUDCA unlike PBA, mitigates protein aggregation efficiently and resists ER and non-ER stress induced HepG2 cell death

Scientific Reports ◽

10.1038/s41598-017-03940-1 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 34

Author(s):

Jagadeesh Kumar Uppala ◽

Amina R. Gani ◽

Kolluru V. A. Ramaiah

Keyword(s):

Cell Death ◽

Protein Aggregation ◽

Er Stress ◽

Hepg2 Cell ◽

Chemical Chaperone

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Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity

eLife ◽

10.7554/elife.43302 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 2

Author(s):

Keisuke Kitakaze ◽

Shusuke Taniuchi ◽

Eri Kawano ◽

Yoshimasa Hamada ◽

Masato Miyake ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Protein Aggregation ◽

Er Stress ◽

Chemical Biology ◽

Chemical Chaperone ◽

Chemical Chaperones ◽

Benzothiazole Derivatives ◽

Chemically Induced ◽

A Cell

The endoplasmic reticulum (ER) is responsible for folding secretory and membrane proteins, but disturbed ER proteostasis may lead to protein aggregation and subsequent cellular and clinical pathologies. Chemical chaperones have recently emerged as a potential therapeutic approach for ER stress-related diseases. Here, we identified 2-phenylimidazo[2,1-b]benzothiazole derivatives (IBTs) as chemical chaperones in a cell-based high-throughput screen. Biochemical and chemical biology approaches revealed that IBT21 directly binds to unfolded or misfolded proteins and inhibits protein aggregation. Finally, IBT21 prevented cell death caused by chemically induced ER stress and by a proteotoxin, an aggression-prone prion protein. Taken together, our data show the promise of IBTs as potent chemical chaperones that can ameliorate diseases resulting from protein aggregation under ER stress.

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Melittin Ameliorates Endotoxin-Induced Acute Kidney Injury by Inhibiting Inflammation, Oxidative Stress, and Cell Death in Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/8843051 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Jung-Yeon Kim ◽

Jaechan Leem ◽

Hyo-Lim Hong

Keyword(s):

Acute Kidney Injury ◽

Cell Death ◽

Structural Damage ◽

Biological Activities ◽

Kidney Injury ◽

Antioxidant Defenses ◽

Tubular Damage ◽

Related Factor ◽

Nuclear Factor ◽

Lps Treatment

Sepsis-related acute kidney injury (AKI) is a worldwide health problem, and its pathogenesis involves multiple pathways. Lipopolysaccharide (LPS) is an endotoxin that induces systemic inflammatory responses. Melittin, a main constituent of bee venom, exerts several biological activities such as antioxidant, anti-inflammatory, and antiapoptotic actions. However, whether melittin protects against endotoxin-induced AKI remains undetermined. Here, we aimed to examine the potential action of melittin on LPS-induced renal injury and explore the mechanisms. We showed that acute renal failure and structural damage after injection of LPS were markedly attenuated by administration of melittin. The peptide also suppressed expression of markers of direct tubular damage in kidneys of the LPS-treated mice. Mechanistically, melittin reduced systemic and renal levels of cytokines and inhibited renal accumulation of immune cells with concomitant suppression of nuclear factor kappa-B pathway. Increased amounts of lipid peroxidation products after LPS treatment were largely decreased by melittin. Additionally, the peptide decreased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and enhanced nuclear factor erythroid-2-related factor 2-mediated antioxidant defenses. Moreover, melittin inhibited apoptotic and necroptotic cell death after LPS treatment. Lastly, we showed that melittin improved the survival rate of LPS-injected mice. These results suggest that melittin ameliorates endotoxin-induced AKI and mortality through inhibiting inflammation, oxidative injury, and apoptotic and necroptotic death of tubular epithelial cells.

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Faculty Opinions recommendation of C-type lectin Mincle mediates cell death-triggered inflammation in acute kidney injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.738504385.793580734 ◽

2020 ◽

Author(s):

Takeshi Tsubata

Keyword(s):

Acute Kidney Injury ◽

Cell Death ◽

Kidney Injury

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Pathogenesis of Acute Kidney Injury

Kidney Protection ◽

10.1093/med/9780190611620.003.0002 ◽

2019 ◽

pp. 11-20

Author(s):

David P. Basile ◽

Babu J. Padanilam

Keyword(s):

Acute Kidney Injury ◽

Cell Death ◽

Renal Function ◽

Fatty Acid ◽

Interstitial Fibrosis ◽

Kidney Injury ◽

Acid Oxidation ◽

Clinical Disorder ◽

Successful Recovery ◽

Multiple Issues

Acute kidney injury represents a significant clinical disorder associated with a rapid loss of renal function following a variety of potential insults. This chapter reviews multiple issues related to the pathophysiology of AKI with an emphasis on studies from animal models. Early responses following kidney injury include impaired hemodynamic and bioenergetic responses. Reductions in renal ATP levels occur as a result of compromised fatty acid oxidation and impaired compensation by glycolysis. Sustained reductions in perfusion contribute to extension of AKI characterized by complex inflammatory and cellular injury responses, often leading to cell death. Concurrently, the kidney displays an elegant repair response, leading to successful recovery in most cases, characterized in part by epithelial cell growth, while maladaptive or incomplete recovery of tubules or capillaries can predispose the development of interstitial fibrosis and CKD progression.

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Class IIa HDAC inhibitor TMP195 alleviates lipopolysaccharide-induced acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00405.2020 ◽

2020 ◽

Vol 319 (6) ◽

pp. F1015-F1026

Author(s):

Wei Zhang ◽

Yinjie Guan ◽

George Bayliss ◽

Shougang Zhuang

Keyword(s):

Acute Kidney Injury ◽

Hdac Inhibitor ◽

Cell Apoptosis ◽

Kidney Injury ◽

Tubular Cell ◽

Intercellular Adhesion Molecule ◽

Renal Tubular Cell ◽

Renoprotective Effect ◽

Renal Tubular ◽

Class Iia Hdacs

Sepsis-associated acute kidney injury (SA-AKI) is associated with high mortality rates, but clinicians lack effective treatments except supportive care or renal replacement therapies. Recently, histone deacetylase (HDAC) inhibitors have been recognized as potential treatments for acute kidney injury and sepsis in animal models; however, the adverse effect generated by the use of pan inhibitors of HDACs may limit their application in people. In the present study, we explored the possible renoprotective effect of a selective class IIa HDAC inhibitor, TMP195, in a murine model of SA-AKI induced by lipopolysaccharide (LPS). Administration of TMP195 significantly reduced increased serum creatinine and blood urea nitrogen levels and renal damage induced by LPS; this was coincident with reduced expression of HDAC4, a major isoform of class IIa HDACs, and elevated histone H3 acetylation. TMP195 treatment following LPS exposure also reduced renal tubular cell apoptosis and attenuated renal expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, two biomarkers of tubular injury. Moreover, LPS exposure resulted in increased expression of BAX and cleaved caspase-3 and decreased expression of Bcl-2 and bone morphogenetic protein-7 in vivo and in vitro; TMP195 treatment reversed these responses. Finally, TMP195 inhibited LPS-induced upregulation of multiple proinflammatory cytokines/chemokines, including intercellular adhesion molecule-1, monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-1β, and accumulation of inflammatory cells in the injured kidney. Collectively, these data indicate that TMP195 has a powerful renoprotective effect in SA-AKI by mitigating renal tubular cell apoptosis and inflammation and suggest that targeting class IIa HDACs might be a novel therapeutic strategy for the treatment of SA-AKI that avoids the unintended adverse effects of a pan-HDAC inhibitor.

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Programmed cell death protein 1 inhibitor treatment is associated with acute kidney injury and hypocalcemia: meta-analysis

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfy105 ◽

2018 ◽

Vol 34 (1) ◽

pp. 108-117 ◽

Cited By ~ 46

Author(s):

Sandhya Manohar ◽

Panagiotis Kompotiatis ◽

Charat Thongprayoon ◽

Wisit Cheungpasitporn ◽

Joerg Herrmann ◽

...

Keyword(s):

Acute Kidney Injury ◽

Cell Death ◽

Programmed Cell Death ◽

Meta Analysis ◽

Kidney Injury ◽

Cell Death Protein ◽

Inhibitor Treatment

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Kidney Inflammation, Injury and Regeneration

International Journal of Molecular Sciences ◽

10.3390/ijms21031164 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1164 ◽

Cited By ~ 4

Author(s):

Baer ◽

Koch ◽

Geiger

Keyword(s):

Acute Kidney Injury ◽

Cell Death ◽

Kidney Injury ◽

Kidney Cells

Damage to kidney cells can occur due to a variety of ischemic and toxic insults and leads to inflammation and cell death, which can result in acute kidney injury (AKI) [...]

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Cell Death Patterns Due to Warm Ischemia or Reperfusion in Renal Tubular Epithelial Cells Originating from Human, Mouse, or the Native Hibernator Hamster

Biology ◽

10.3390/biology7040048 ◽

2018 ◽

Vol 7 (4) ◽

pp. 48 ◽

Cited By ~ 5

Author(s):

Theodoros Eleftheriadis ◽

Georgios Pissas ◽

Georgia Antoniadi ◽

Vassilios Liakopoulos ◽

Ioannis Stefanidis

Keyword(s):

Lipid Peroxidation ◽

Acute Kidney Injury ◽

Cell Death ◽

Epithelial Cells ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Human Cells ◽

Tubular Epithelial Cells

Ischemia–reperfusion injury contributes to the pathogenesis of many diseases, with acute kidney injury included. Hibernating mammals survive prolonged bouts of deep torpor with a dramatic drop in blood pressure, heart, and breathing rates, interspersed with short periods of arousal and, consequently, ischemia–reperfusion injury. Clarifying the differences under warm anoxia or reoxygenation between human cells and cells from a native hibernator may reveal interventions for rendering human cells resistant to ischemia–reperfusion injury. Human and hamster renal proximal tubular epithelial cells (RPTECs) were cultured under warm anoxia or reoxygenation. Mouse RPTECs were used as a phylogenetic control for hamster cells. Cell death was assessed by both cell imaging and lactate dehydrogenase (LDH) release assay, apoptosis by cleaved caspase-3, autophagy by microtubule-associated protein 1-light chain 3 B II (LC3B-II) to LC3B-I ratio, necroptosis by phosphorylated mixed-lineage kinase domain-like pseudokinase, reactive oxygen species (ROS) fluorometrically, and lipid peroxidation, the end-point of ferroptosis, by malondialdehyde. Human cells died after short periods of warm anoxia or reoxygenation, whereas hamster cells were extremely resistant. In human cells, apoptosis contributed to cell death under both anoxia and reoxygenation. Although under reoxygenation, ROS increased in both human and hamster RPTECs, lipid peroxidation-induced cell death was detected only in human cells. Autophagy was observed only in human cells under both conditions. Necroptosis was not detected in any of the evaluated cells. Clarifying the ways that are responsible for hamster RPTECs escaping from apoptosis and lipid peroxidation-induced cell death may reveal interventions for preventing ischemia–reperfusion-induced acute kidney injury in humans.

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