Imoxin attenuates high fructose‐induced oxidative stress and apoptosis in renal epithelial cells via downregulation of protein kinase R pathway

Kalra, Jaspreet; Mangali, Suresh Babu; Bhat, Audesh; Dhar, Indu; Udumula, Mary Priyanka; Dhar, Animesh

doi:10.1111/fcp.12352

Cited by 9 publications

(11 citation statements)

References 36 publications

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“…However, no studies have been done so far to explore the role of PKR in hypertension related renal damage. Previously, we have reported the association of PKR in endothelial dysfunction, cardiovascular remodeling and renal inflammation [18,19]. In continuation with our previous study, we establish the role of PKR in NG-Nitro-L-arginine Methyl Ester, Hydrochloride (L-NAME) induced renal damage.…”

Section: Introductionsupporting

confidence: 83%

Up-regulation of PKR pathway contributes to L-NAME induced hypertension and renal damage

Kalra

Bhat

Jadhav

et al. 2020

Heliyon

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Hypertension induced kidney damage is often associated with fibrosis and tubular apoptosis. Doublestranded protein kinase (PKR) is a well recognized inducer of inflammation and apoptosis. However, role of PKR in hypertension coupled renal damage is still not explored. Therefore here we sought to investigate the role of PKR in the pathogenesis of L-NAME induced hypertension and renal damage in Wistar rats and the underneath molecular mechanism. Methods: L-NAME (40 mg/kg, p.o) and imoxin (0.5 mg/kg, i.p) was given to Wistar rats for 4 weeks. Increased eNOS expression, serum creatinine, BUN and changes in mean arterial pressure confirmed for hypertensive renal damage. Western blot and immunohistochemistry was carried out for PKR and markers for fibrosis and apoptosis. Morphological alterations were assessed by H&E staining. Sirius red and Masson's Trichrome staining was performed for collagen and fibrosis. TUNEL assay was done for tubular cell death and apoptosis. Results: Increased expression of PKR and its downstream markers were reported in L-NAME rats, attenuation was observed with imoxin treatment. L-NAME treated rats showed a significant increase in MAP, serum calcium, creatinine and BUN along with the significant morphological changes, attenuation was reported with the imoxin treatment. Conclusion: PKR is a core contributor in the pathogenesis of L-NAME induced renal damage and tubular apoptosis. Therapeutically targeting of PKR could be an attractive approach to treat the renal complications associated with hypertension.

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Section: Introductionsupporting

confidence: 83%

Up-regulation of PKR pathway contributes to L-NAME induced hypertension and renal damage

Kalra

Bhat

Jadhav

et al. 2020

Heliyon

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“…PKR is known to mediate the antiviral effects of interferons in leukocytes, regulate cell inflammation, proliferation and apoptosis in uninfected cell types and may thus be involved in a variety of CVD associated with chronic inflammation. 19,23,26 Previous studies have shown SFAs induce apoptosis in many cell types and is associated with the development of metabolic disorders, such as diabetes, hypertension and heart disease. 4,[28][29][30][31][32][33][34][35][36] To know whether PKR inhibition prevents PA-induced apoptosis, we determined apoptosis by FACS analysis (Figure 2A and 2B) and caspase-3 expression (Figure 2C and 2D), we observed the inhibition of PKR could prevent apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Cells were incubated for 24 hours with different treatments and harvested under 4‐8°C conditions. Apoptosis assay was performed using Annexin V/PI apoptosis kit by flow cytometry as mentioned previously …”

Section: Methodsmentioning

confidence: 99%

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Inhibition of protein kinase R protects against palmitic acid–induced inflammation, oxidative stress, and apoptosis through the JNK/NF‐kB/NLRP3 pathway in cultured H9C2 cardiomyocytes

Mangali

Bhat

Udumula

et al. 2018

J of Cellular Biochemistry

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Background and Purpose: Double-stranded RNA-dependent protein kinase (PKR) is a critical regulator of apoptosis, oxidative stress, and inflammation under hyperlipidemic and insulin resistance conditions. Saturated free fatty acids, such as palmitic acid (PA), are known inducers of apoptosis in numerous cell types. However, the underlying molecular mechanism is not fully understood. The aim of the present study was to examine the effect of PA on cultured rat H9C2 cardiac myocytes cells and to investigate the PKR mediated harmful effects of PA in vitro in cultured cardiomyocytes.Experimental Approach: PKR expression was determined by immunofluorescence and immunoblotting. Oxidative stress and apoptosis were determined by flow cytometry and assay kits. The expression of different gene markers of apoptosis, oxidative stress, and inflammation were measured by Western blot analysis and reverse transcription polymerase chain reaction.Key Results: PKR expression, reactive oxygen species levels as well as apoptosis were increased in PA-treated cultured H9C2 cardiomyocytes. The harmful effects of PA were attenuated by a selective PKR inhibitor, C16.Moreover, we observed that upregulation of c-Jun N-terminal kinase (JNK), nuclear factor-kB (NF-kB) and NACHT, LRR and PYD domains-containing protein 3 (NLRP3) pathways is associated with increased expression of interleukin 6 and tumor necrosis factor-α in PA-treated cardiomyocytes and attenuation by a selective PKR inhibitor.Conclusion and Implications: Our study reports, for the first time, that PKRmediated harmful effects of PA in cultured cardiomyocytes via activation of

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“…Clearly, it could be hypothesized that specific pharmacological inhibitors against particular RNA-RBPs would restore normal insulin signaling, glucose and lipid metabolism, and ameliorate inflammation and fibrosis of metabolic tissues, such as is observed in obesity-induced steatohepatitis. As a proof of principle, small chemical inhibitors were tested to block the activity of PKR, such as imoxin and 2-aminopurine (199, 200), and when used under immune-metabolic stress conditions resulted in improvements in immune-metabolic phenotypes in a mouse model (156). Additionally, new chemical agents are being developed that antagonize the miRNA-Ago2 protein complex, including anti-miRNA–Ago2 and tiny locked nucleic acids (LNAs), by binding to the active site of Ago2 protein and seed region of miRNAs, thereby resulting in functional inhibition of Ago2-mediated miRNAs (201–203).…”

Section: Introductionmentioning

confidence: 99%

RNAs and RNA-Binding Proteins in Immuno-Metabolic Homeostasis and Diseases

Salem

Vonberg

Borra

et al. 2019

Front. Cardiovasc. Med.

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The increasing prevalence of worldwide obesity has emerged as a major risk factor for type 2 diabetes (T2D), hepatosteatosis, and cardiovascular disease. Accumulating evidence indicates that obesity has strong inflammatory underpinnings tightly linked to the development of metabolic diseases. However, the molecular mechanisms by which obesity induces aberrant inflammation associated with metabolic diseases are not yet clearly defined. Recently, RNAs have emerged as important regulators of stress responses and metabolism. RNAs are subject to changes in modification status, higher-order structure, and cellular localization; all of which could affect the affinity for RNA-binding proteins (RBPs) and thereby modify the RNA-RBP networks. Proper regulation and management of RNA characteristics are fundamental to cellular and organismal homeostasis, as well as paramount to health. Identification of multiple single nucleotide polymorphisms (SNPs) within loci of fat mass- and obesity-associated protein (FTO) gene, an RNA demethylase, through genome-wide association studies (GWAS) of T2D, and functional assessments of FTO in mice, support the concept that disruption in RNA modifications leads to the development of human diseases including obesity and metabolic disorder. In obesity, dynamic alterations in modification and localization of RNAs appear to modulate the RNA-RBP networks and activate proinflammatory RBPs, such as double-stranded RNA (dsRNA)-dependent protein kinase (PKR), Toll-like receptor (TLR) 3 and TLR7, and RNA silencing machinery. These changes induce aberrant inflammation and the development of metabolic diseases. This review will describe the current understanding of the underlying causes of these common and altered characteristics of RNA-RBP networks which will pave the way for developing novel approaches to tackle the pandemic issue of obesity.

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Imoxin attenuates high fructose‐induced oxidative stress and apoptosis in renal epithelial cells via downregulation of protein kinase R pathway

Cited by 9 publications

References 36 publications

Up-regulation of PKR pathway contributes to L-NAME induced hypertension and renal damage

Up-regulation of PKR pathway contributes to L-NAME induced hypertension and renal damage

Inhibition of protein kinase R protects against palmitic acid–induced inflammation, oxidative stress, and apoptosis through the JNK/NF‐kB/NLRP3 pathway in cultured H9C2 cardiomyocytes

RNAs and RNA-Binding Proteins in Immuno-Metabolic Homeostasis and Diseases

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