Luteolin supplementation ameliorates cobalt-induced oxidative stress and inflammation by suppressing NF-кB/Kim-1 signaling in the heart and kidney of rats

https://doi.org/10.1016/j.etap.2020.103488Get rights and content

Highlights

  • Cobalt induces oxidative stress and up-regulation of NF-кB in heart and kidneys of rats.

  • Luteolin’s suppression of cobalt-induced injury involved suppression of oxidative damage and down-regulation of NF-кB.

  • Luteolin exhibited marked anti-inflammatory activity with reduction of serum myeloperoxidase activity.

Abstract

Cobalt-induced cardiomyopathy and renal toxicity have been reported in workers in processing plants, hard metal industries, diamond polishing and manufacture of ceramics. This study was designed to investigate the influence of Luteolin supplementation on cobalt-induced cardiac and renal toxicity in rats. Exposure of rats to cobalt chloride (CoCl2) alone caused significant (p < 0.05) increases in cardiac and renal H2O2, malondialdehyde (MDA) and nitric oxide (NO), along with increased serum myeloperoxidase (MPO) activity. In addition, there were significant (p < 0.05) reductions in cardiac and renal glutathione peroxidase (GPx), glutathione S-transferase (GST) and reduced glutathione (GSH). CoCl2 induced higher immuno-staining of nuclear factor kappa beta (NF-κB) in the heart and kidneys, and the kidney injury molecule (Kim-1) in the kidneys. Treatment with Luteolin or Gallic acid produced significant reversal of the oxidative stress parameters with reductions in NF-κB and Kim-1 expressions, leading to suppression of histopathological lesions observed in the tissues.

Introduction

Environmental exposure to cobalt is common because of its use in industrial processes, nutritional supplements, recreational or medicinal products or implanted medical devices made of high-performance, wear-resistant cobalt alloys (Unice et al., 2012; Packer, 2016). Previous reports indicated that the production of refined cobalt has increased steadily the world over (IARC, 2006), with production figures at about 123,000 tons of world cobalt mine production and 91,300 tons of cobalt refinery production in 2014 (Shedd, 2014), thus, increasing the risk of environmental and industrial exposures. Because of its ability to stimulate red blood cell production, cobalt has been used historically to treat refractory anaemia and is now increasingly used by athletes to increase red cell mass and boost exercise performance (Lippi et al., 2006). Exposure to high concentrations of cobalt has been reported to cause cardiomyopathies in workers involved in processing plants, hard-metal, diamond polishing and ceramic industries (Sauni et al., 2017), and in patients undergoing hip arthroplasty with cobalt implants (Umar et al., 2019).

Similar to cardiomyopathies that were documented in heavy-beer drinkers, reported cases of industrial cobalt exposure are characterized by a sub-acute onset of heart failure, sinus tachycardia, pericardial effusions, polycythaemia, cyanosis, and hypotension (Packer, 2016). Additionally, nephrotoxic effects have also been observed in excessive exposure to cobalt (Garoui et al., 2012). The kidney is an important target of heavy metal toxicity because of its ability to reabsorb and accumulate divalent metal ions. Studies in orthopaedic metal toxicity identified that metal ions such as cobalt and chromium emanating from implanted devices are excreted by the kidneys and have the potential to induce tubular necrosis (Keegan et al., 2007).

Management of cobalt toxicity in exposed individuals have included chelation therapy with agents that bind metals and aid its renal excretion, thus, reducing the metal ion load in the body, while the removal of causative implant remains the recommended treatment in patients undergoing arthroplasty (Corradi et al., 2011). However, chelation therapy is limited as it relies on renal excretion of the metal and exposure to cobalt itself can lead to renal impairment (Umar et al., 2019). Recently, several investigators have turned attention to the use of natural compounds in the protection of biological system against toxic effects of xenobiotic exposures (Wu et al., 2017).

Luteolin is a flavone commonly found in many fruits and vegetables with reported antioxidant, anti-inflammatory and anticancer activities (Francisco et al., 2016). Like many other flavonoids, luteolin is known to exert antioxidant activities by forming chelate complexes with metal ions, thus, preventing the latter’s participation in formation of free radicals (Symonowicz and Kolanek, 2012), However, its main antioxidant actions against metal toxicity, perhaps involve the regulation of heavy-metal induced generation of reactive oxygen species (Choi, 2011), via direct scavenging of free radicals.

Luteolin has been reported to offer cardio-protection through several mechanisms (Luo et al., 2017). In the same vein, luteolin was found to improve renal function in rats subjected to ischemia-reperfusion injury by different mechanisms including reduction of oxidative stress, inflammation and renal cell apoptosis (Hong et al., 2017). However, the role of luteolin treatment on cobalt-induced cardiotoxicity and nephrotoxicity, as well as the possible mechanisms involved, has not been explored. Therefore, the present study was designed to assess the protective effects of luteolin on cardiac and renal damage induced by cobalt chloride exposure and also explore possible molecular mechanisms of its action in a rat experimental model. We have previously demonstrated the protective role of gallic acid against cobalt-induced cardio-renal toxicities (Akinrinde et al., 2016a, b). For comparison, gallic acid has been included as a standard in this study as a basis to evaluate the effects of luteolin.

Section snippets

Chemicals, reagents and antibodies

Luteolin, gallic acid, thiobarbituric acid (TBA), trichloro acetic acid (TCA), 1, 2-dichloro-4-nitrobenzene (CDNB), sodium hydroxide, xylenol orange, potassium hydroxide, reduced glutathione (GSH), and hydrogen peroxide (H2O2) were purchased from Sigma (St. Louis, Missouri). Cobalt chloride hexahydrate (CoCl2·6H2O) was purchased from Tianjin Kermel Chemical Reagent Co., China. Normal goat serum, Biotinylated antibody and horse radish peroxidase (HRP) System was purchased from KPL, Inc.

CRediT authorship contribution statement

Ademola Adetokunbo Oyagbemi: Conceptualization, Resources, Software, Writing - review & editing. Akinleye Stephen Akinrinde: Conceptualization, Methodology, Resources, Investigation, Formal analysis, Writing - original draft, Writing - review & editing. Olamide Elizabeth Adebiyi: Methodology, Resources, Writing - review & editing. Theophilus Aghogho Jarikre: Methodology, Visualization, Writing - review & editing. Temidayo Olutayo Omobowale: Resources, Writing - review & editing. Olufunke Eunice

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The authors are grateful for the technical assistance provided by Mr. O. Agboola of the Department of Veterinary Physiology and Biochemistry, University of Ibadan. This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

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