Myoglobin Induces Vascular Cell Adhesion Molecule-1 Expression through c-Src Kinase-Activator Protein-1/Nuclear Factor-ĸB Pathways

Kim, Sang Hyun; Chang, Jai Won; Kim, Soon Bae; Park, Su Kil; Park, Jung Sik; Lee, Sang Koo

doi:10.1159/000254391

Cited by 13 publications

(6 citation statements)

References 78 publications

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“…After muscle injury, released myoglobin from cells is accumulated in the renal tubules where it leads to the formation HDAC6 inhibition of reactive oxygen species that causes renal injury (47). ROS can promote lipid peroxidation of membrane fatty acids (6,20) and induce MDA synthesis, which mediates alterations of proteins and DNA (31,39). In contrast, rhabdomyolysis can result in decreased SOD activity in kidney tissues (14).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury

Shi

Tang

et al. 2017

American Journal of Physiology-Renal Physiology

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Histone deacetylase 6 (HDAC6) inhibition has been reported to protect against ischemic stroke and prolong survival after sepsis in animal models. However, it remains unknown whether HDAC6 inhibition offers a renoprotective effect after acute kidney injury (AKI). In this study, we examined the effect of tubastatin A (TA), a highly selective inhibitor of HDAC6, on AKI in a murine model of glycerol (GL) injection-induced rhabdomyolysis. Following GL injection, the mice developed severe acute tubular injury as indicated by renal dysfunction; expression of neutrophil gelatinase-associated lipocalin (NGAL), an injury marker of renal tubules; and an increase of TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells. These changes were companied by increased HDAC6 expression in the cytoplasm of renal tubular cells. Administration of TA significantly reduced serum creatinine and blood urea nitrogen levels as well as attenuated renal tubular damage in injured kidneys. HDAC6 inhibition also resulted in decreased expression of NGAL, reduced apoptotic cell, and inactivated caspase-3 in the kidney after acute injury. Moreover, injury to the kidney increased phosphorylation of nuclear factor (NF)-κB and expression of multiple cytokines/chemokines including tumor necrotic factor-α and interleukin-6 and monocyte chemoattractant protein-1, as well as macrophage infiltration. Treatment with TA attenuated all those responses. Finally, HDAC6 inhibition reduced the level of oxidative stress by suppressing malondialdehyde (MDA) and preserving expression of superoxide dismutase (SOD) in the injured kidney. Collectively, these data indicate that HDAC6 contributes to the pathogenesis of rhabdomyolysis-induced AKI and suggest that HDAC6 inhibitors have therapeutic potential for AKI treatment.

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Section: Discussionmentioning

confidence: 99%

Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury

Shi

Tang

et al. 2017

American Journal of Physiology-Renal Physiology

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“…These radical species promote lipid peroxidation of membrane fatty acids [11,12] and induce malondialdehyde synthesis, which mediates alterations of proteins and DNA [13,14]. Lipid peroxidation of fatty acids results in the production of F2-isoprostanes, as observed in the urine of affected patients [15].…”

Section: +mentioning

confidence: 99%

Molecular Mechanisms and Novel Therapeutic Approaches to Rhabdomyolysis-Induced Acute Kidney Injury

Panizo

Rubio‐Navarro

Amaro-Villalobos

et al. 2015

Kidney Blood Press Res

150

165

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Rhabdomyolysis is a syndrome caused by injury to skeletal muscle that usually leads to acute kidney injury (AKI). Rhabdomyolysis has been linked to different conditions, including severe trauma and intense physical exercise. Myoglobin-induced renal toxicity plays a key role in rhabdomyolysis-associated kidney damage by increasing oxidative stress, inflammation, endothelial dysfunction, vasoconstriction, and apoptosis. New drugs that target the harmful effects of myoglobin have been recently developed, and some have been proven to be successful in animal models of acute renal failure secondary to rhabdomyolysis. This review aims to provide a comprehensive and updated overview of the pathological mechanisms of renal damage and describes new therapeutic approaches to this condition based on novel compounds that target key pathways involved in myoglobin-mediated kidney damage.

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“…In tested transcription factors, only c-Jun was activated by AGE treatment in PTC. c-Jun is one of the downstream factors of ERK 1/2 54,55 and forms AP-1 complex, which promotes AGT transcription. 24 STAT3 and NF-κB, which can be activated by AGE 8,12,13 and have been identified as AGT regulating transcription factors in PTC, 21–23 failed to demonstrate activation during AGE treatment under our experimental conditions.…”

Section: Discussionmentioning

confidence: 99%

Advanced Glycation End Products Stimulate Angiotensinogen Production in Renal Proximal Tubular Cells

Garagliano

Katsurada

Miyata

et al. 2019

The American Journal of the Medical Sciences

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Background: Elevated advanced glycation end products (AGE) in diabetes mellitus (DM) are implicated in the progression of DM-associated tissue injury, including diabetic nephropathy. The intrarenal renin-angiotensin system, in particular augmentation of angiotensinogen (AGT) in proximal tubular cells (PTC), plays a crucial role in the development of diabetic nephropathy. This study investigated hypothesis that AGE stimulates AGT production in PTC. Materials and Methods: Urinary AGT and AGE levels in streptozotocin-induced DM mice were measured by enzyme-linked immunosorbent assays. AGT expression and secretion were evaluated in cultured rat PTC receiving 0-200 μg/ml AGE-BSA treatments for 24 hours. Furthermore, intracellular signaling pathways activated by AGE were elucidated. Results: DM mice exhibited greater urinary AGT and AGE levels compared to control mice (AGT: 21.6 ± 5.5 ng/day vs. 190.1 ± 57.8 ng/day, AGE: 139.1 ± 21.6 μg/day vs. 332.8 ± 102.7 μg/day). In cultured PTC, treatment with AGE-BSA enhanced AGT mRNA expression (3.43 ± 0.11-fold compared to control), intracellular AGT protein levels (3.60 ± 0.38-fold), and secreted AGT levels (2.11 ± 0.18-fold). On the other hand, AGT levels were not altered in PTC receiving nonglycated BSA. Recombinant soluble AGE receptor, which competes with endogenous AGE receptor, diminished the AGE-induced AGT upregulation, suggesting that AGE-BSA stimulates AGT expression via activation of the AGE receptor. Enhanced phosphorylation of ERK½ and c-Jun, but not p38 MAP kinase, were observed in AGE-BSA-treated PTC. AGE-induced AGT augmentation was attenuated by an ERK inhibitor. Conclusions: The findings indicate that AGE enhances proximal tubular AGT expression via ERK1/2, which can exacerbate the development of diabetic related kidney injury.

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Myoglobin Induces Vascular Cell Adhesion Molecule-1 Expression through c-Src Kinase-Activator Protein-1/Nuclear Factor-ĸB Pathways

Cited by 13 publications

References 78 publications

Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury

Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury

Molecular Mechanisms and Novel Therapeutic Approaches to Rhabdomyolysis-Induced Acute Kidney Injury

Advanced Glycation End Products Stimulate Angiotensinogen Production in Renal Proximal Tubular Cells

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