Molecular mechanisms underlying attenuation of cisplatin-induced acute kidney injury by epicatechin gallate

Abstract

Cisplatin, a platinum compound, is used as a first-line agent against various forms of solid cancers. Nephrotoxicity is an important adverse effect of cisplatin therapy, which involves increased oxidative stress, inflammation, apoptosis, and activation of the mitogen-activated protein kinase (MAPK) pathway. It is well known that the bioactive compounds present in green tea are used to treat various disorders due to their biological activities. With this background, the present study was aimed to investigate the effect of epicatechin gallate (ECG), a green tea polyphenol, in cisplatin-induced nephrotoxicity in rats. To achieve this, ECG (1.25, 2.5, and 5 mg/kg; intraperitoneal (i.p.)) was administered to male albino Wistar rats for the period of 10 days. On the 7th day, a single i.p. injection of cisplatin (8 mg/kg) was injected into rats to produce kidney injury and the animals were then killed on the 10th day. Cisplatin toxicity was associated with enhanced oxidative stress, impaired renal function along with marked tubular necrosis in Histopathology. Furthermore, cisplatin activated the MAPK pathway, which contributed to inflammation and apoptosis in the kidney of treated rats. In contrast, ECG (5 mg/kg) pretreatment normalized cisplatin-induced oxidative stress, renal function, and histopathological changes. ECG also prevented the activation of the MAPK pathway, and attenuated inflammation and apoptosis in rats. These findings suggest that ECG prevented cisplatin-induced oxidative stress, inflammation, and apoptosis by downregulating the MAPK pathway and resulted in improved renal function.

Flavonoids in Kidney Health and Disease

“…Several flavonoids attenuate cisplatin-induced renal injury in rats and mice, mitigating cisplatin-induced histopathologic alterations and reducing the increases in serum creatinine and blood urea nitrogen. Their mechanism of action involves several pathways of the inflammatory cascade and oxidative perturbations (Tanabe et al, 2012 ; Malik et al, 2015 , 2016 ; Arab et al, 2016 ; Chao et al, 2016 ; He et al, 2016 ; Hassan et al, 2017 ; Huang D. et al, 2017 ; Huang Y. C. et al, 2017 ; Lee et al, 2017 ; Ma et al, 2017 ), including: the downregulation of activated NF-κB p65 protein expression and its downstream effectors (e.g., iNOS and TNF-α), with restoration of the anti-inflammatory IL-10; and reductions in phospho-NF-κB p65 and phospho-P38 MAPK activation and Nrf2 expression in cisplatin-induced renal injury. Flavonoids also downregulated the expression of the apoptotic marker caspase-3, inhibiting cisplatin-induced apoptosis and thereby favoring renal cell survival.…”

Pitavastatin attenuates cisplatin-induced renal injury by targeting MAPK and apoptotic pathways

“…MAPKs act as prominent signal transduction system that mediates cellular response to stressors such as reactive oxygen species, ischaemia and inflammatory cytokines. These findings have been validated by various experiments from our laboratory using rat models . An ideal molecule to treat cisplatin‐induced nephrotoxicity should reverse the aforementioned changes, without blunting its cytotoxic effects on malignant cells.…”

Slower Elimination of Tofacitinib in Acute Renal Failure Rat Models: Contribution of Hepatic Metabolism and Renal Excretion

“…Gentamicin, a representative aminoglycoside antibiotic, induces moderate and reversible acute renal failure [ 32 ], while cisplatin, a chemotherapeutic drug, causes more severe and irreversible acute renal failure [ 33 ]. Both drugs accumulate in the renal tubule; produce reactive oxygen species (ROS) such as superoxide anion, hydrogen peroxide, and hydroxyl radical; and result in the induction of tubular necrosis and/or apoptosis [ 34 , 35 , 36 ]. The impaired renal function caused by these drugs was fully demonstrated, but liver damage did not seem to be serious in our preliminary study.…”