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

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.

Impact of Human Umbilical Cord Blood Mononuclear Cells on Gentamicin-Induced Renal Injury and Genotoxicity in Rats

“…Hence, we suggested that HUCB-MNCs could restore the normal expression of Kim-1 level by minimizing the observed renal damage. It has been proposed that inflammation plays a role in the pathogenesis of GM-induced nephrotoxicity ( 43 ).…”

“…Some animal models have been used to investigate possible pathways for HUCB MNCs' protective properties ( 26 , 35 , 43 , 58 – 60 ). Most SCs were gradually transferred to injured sites or the liver, spleen, kidney, and bone marrow ( 61 , 62 ) to recruit SCs to repair the damage caused by release factors ( 63 ).…”

“…Previous experiments have linked the timing and route of SCs administration to the protective effect against AKI (58). Some animal models have been used to investigate possible pathways for HUCB MNCs' protective properties (26,35,43,(58)(59)(60). Most SCs were gradually transferred to injured sites or the liver, spleen, kidney, and bone marrow (61,62) to recruit SCs to repair the damage caused by release factors (63).…”

Investigation of the Effect of Lycopene, Hesperidin, Essential Oil and their Relative Nano-Formulation Form on Experimentally Obese –Induced Rats

“…While, hesperidin significantly increases the level of α-Klotho (α-KL) in serum, liver, and kidney tissues and significantly reduces the levels of blood urea nitrogen (BUN) and creatinine in fibroblast growth factor-23 (FGF-23) in kidney tissues and serum [49]. On the other hand, D-limonene of essential oil orange peels may increase GFR following the amelioration of renal histopathological alterations and finally lowering serum levels of urea and creatinine [50]. Effect of native lycopene, hesperidin, essential oil and their nano-formulation forms on liver function.…”

“…While, hesperidin significantly increases the level of α-Klotho in serum, liver, and kidney tissues of diabetic rats, and consequently significantly reduce the levels of AST and ALT, so it helps in maintaining normal function by accelerating the regenerative capacity of liver cells [54]. The antioxidative protective effects of essential oil might be associated with its abilities to scavenge ROS and/or induce the gene expression of antioxidant enzymes [50].…”