D-Limonene Alleviates Acute Kidney Injury Following Gentamicin Administration in Rats: Role of NF-κB Pathway, Mitochondrial Apoptosis, Oxidative Stress, and PCNA.

Esmaeel Babaeenezhad,Forouzan Hadipour Moradi,Hassan Ahmadvand,Maryam Nasri,Omid Dezfoulian,Sobhan Rahimi Monfared,Abdolhakim Amini,Mohammad Davood Fattahi,Jos L Quiles

doi:10.1155/2021/6670007

Abstract

Clinical application of gentamicin (GM) is well known to be associated with the development of acute kidney injury (AKI). This study was the first to investigate the possible protective effects of D-limonene (D-lim) on AKI following GM administration in rats. 32 rats arranged in four groups (n = 8): (1) the control group received saline intraperitoneally (0.5 ml/day) and orally (0.5 ml/day), (2) the D-lim group received D-lim (100 mg/kg) orally and saline (0.5 ml/day) intraperitoneally, (3) the GM group received GM (100 mg/kg/day) intraperitoneally and saline (0.5 ml/day) orally, and (4) the treated group received intraperitoneal GM (100 mg/kg) and oral D-lim (100 mg/kg). All treatments were performed daily for 12 consecutive days. Results revealed that D-lim ameliorated GM-induced AKI, oxidative stress, mitochondrial apoptosis, and inflammation. D-lim showed nephroprotective effects as reflected by the decrease in serum urea and creatinine and improvement of renal histopathological changes. D-lim alleviated GM-induced oxidative stress by increasing the activities of renal catalase, serum and renal glutathione peroxidase, and renal superoxide dismutase and decreasing renal malondialdehyde and serum nitric oxide levels. Intriguingly, D-lim suppressed mitochondrial apoptosis by considerably downregulating Bax and caspase-3 (Casp-3) mRNA and protein expressions and markedly enhancing Bcl2 mRNA and protein expressions. Furthermore, D-lim significantly decreases GM-induced inflammatory response through downregulation of NF-κB, IL-6, and TNF-α mRNA and/or protein expressions and decrease in renal myeloperoxidase activity. Finally, D-lim remarkably downregulated PCNA protein expression in the treated group compared with the GM group. In brief, this study showed that D-lim alleviated AKI following GM administration in rats, partially through its antioxidant, anti-inflammatory, and antiapoptotic activities as well as downregulation of PCNA expression.

Highlights

Gentamicin (GM) is an aminoglycoside antibiotic, which is clinically beneficial against infections induced by Gramnegative bacteria
It has been suggested that different factors such as mitochondrial dysfunction, oxidative stress, NF-κB activation, inflammation, apoptosis, necrosis, phospholipidosis, and inducible nitric oxide synthase activation are involved in the pathogenesis of GM-induced acute kidney injury (AKI) [7]
We investigated the effects of D-lim on oxidative stress and inflammatory biomarkers, mitochondrial apoptosis, Proliferating cell nuclear antigen (PCNA) expression, and histopathological alterations in a rat model of GM-induced AKI

Summary

Introduction

Gentamicin (GM) is an aminoglycoside antibiotic, which is clinically beneficial against infections induced by Gramnegative bacteria. In spite of GM’s valuable role in treating various bacterial infections, its clinical application induces acute kidney injury (AKI), and the utilization is restricted in clinical trials. It is well known that GM causes dose-dependent nephrotoxicity [1,2,3,4], which is related to its accumulation in the renal proximal convoluted tubules. Nephrotoxicity is distinguished by functional and morphological changes in the kidney such as elevated blood urea nitrogen and creatinine (Cr) in serum, declined glomerular filtration rate (GFR), edema, and acute injury in proximal tubules [5, 6]. The underlying mechanisms involved in the pathogenesis of GM-induced AKI are still not well known. It has been suggested that different factors such as mitochondrial dysfunction, oxidative stress, NF-κB activation, inflammation, apoptosis, necrosis, phospholipidosis, and inducible nitric oxide synthase (iNOS) activation are involved in the pathogenesis of GM-induced AKI [7]

Methods

Results

Conclusion