Farrerol Attenuates Cisplatin-Induced Nephrotoxicity by Inhibiting the Reactive Oxygen Species-Mediated Oxidation, Inflammation, and Apoptotic Signaling Pathways

Abstract

Cisplatin is a chemotherapy drug that is often used in clinical practice, but its frequent use often leads to nephrotoxicity. Therefore, we urgently need a drug that reduces the nephrotoxicity induced by cisplatin. Farrerol reportedly has antioxidant potential, but its renal protective effects and potential mechanisms remain unclear. In this study, we used both cell and mouse models to determine the mechanism of farrerol in cisplatin-induced nephrotoxicity. The in vitro experiments revealed that farrerol improved cisplatin-induced nephrotoxicity and reactive oxygen species (ROS) production via nuclear factor erythrocyte 2-related factor 2 (Nrf2) activation. Moreover, farrerol effectively activated Nrf2 and subsequently increased the expression of Nrf2-targeted antioxidant enzymes, including heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase-1 (NQO1), but inhibited Kelch-like ECH-associated protein 1 (Keap1) and NADPH oxidase type 4 (NOX4). Furthermore, farrerol attenuated the phosphorylation of C-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein kinase (p38); the activation of phosphorylated nuclear factor-κB (p-NF-κB) and nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3); and the expression of phosphorylated p53 (p-p53), Bax, and cleaved caspase-3. In vivo, farrerol significantly improved cisplatin-induced renal damage, as demonstrated by the recovery of blood urea nitrogen (BUN), serum creatinine (SCr), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and pathological damage. Moreover, farrerol inhibited inflammatory and apoptotic protein expression in vivo. Notably, farrerol exerted slight protection in Nrf2-knockout mice compared with wild-type mice. These findings indicate that farrerol can effectively activate Nrf2 and can serve as a therapeutic target in the treatment of acute kidney injury (AKI).

Loganin Attenuates the Severity of Acute Kidney Injury Induced by Cisplatin through the Inhibition of ERK Activation in Mice

“…The administration of loganin inhibited the activation of ERK 1/2, but not JNK, p38, and NF-κB, and we assumed that the inhibition of ERK 1/2 signaling would be beneficial to reno-protection against cisplatin ( Figure 5 ). ERK 1/2 signaling is reported to be associated with inflammation and cell death in AKI [ 25 , 48 , 49 , 50 ]. The inactivation of ERK 1/2 attenuated the severity of cisplatin-induced AKI by reducing the expression of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α [ 50 ].…”

Heme Oxygenase 1: A Defensive Mediator in Kidney Diseases

“…For example, HO-1 induction has been thoroughly studied to prevent cisplatin toxicity [ 8 , 23 , 94 , 202 , 203 , 204 ], which still frequently leads to acute kidney injury through glomerular, vascular and tubular damage [ 329 ]. Different molecules which increase HO-1 expression have been studied to prevent cisplatin-induced apoptosis and inflammation in the kidneys of mouse or rat models: microRNA-140-5p [ 206 ], JQ1 [ 207 ], farrerol [ 208 ], zinc oxide nanoparticles [ 209 ], human growth factor [ 210 ], bardoxolone methyl [ 205 ] and capsaicin (an active component of chili peppers) [ 211 ] have all been studied in this regard. Unfortunately, only a few of these articles reported upon the effect of these molecules on the proapoptotic, antitumoral action of cisplatin on tumoral cells [ 207 ], which is the major stumbling block for their use in offsetting iatrogenic renal damage in cancer patients.…”

Protection against acute renal injury by naturally occurring medicines which act through Nrf2 signaling pathway

“…Not only that, HO‐1 induced by Nrf2 also stabilizes IκBα (An & Shang, 2018). Interestingly, Keap1 is not only an inhibitor of Nrf2, but also inhibits the activation of p65, the NF‐κB compound molecule, and thus inhibits NF‐κB (Ma et al., 2019).…”