Mitochondrial Modulation by Epigallocatechin 3-Gallate Ameliorates Cisplatin Induced Renal Injury through Decreasing Oxidative/Nitrative Stress, Inflammation and NF-kB in Mice

Abstract

Cancer chemotherapy drug cisplatin is known for its nephrotoxicity. The aim of this study is to investigate whether Epigallocatechin 3-Gallate (EGCG) can reduce cisplatin mediated side effect in kidney and to understand its mechanism of protection against tissue injury. We used a well-established 3-day cisplatin induced nephrotoxicity mice model where EGCG were administered. EGCG is a major active compound in Green Tea and have strong anti-oxidant and anti-inflammatory properties. EGCG protected against cisplatin induced renal dysfunction as measured by serum creatinine and blood urea nitrogen (BUN). EGCG improved cisplatin induced kidney structural damages such as tubular dilatation, cast formation, granulovaculoar degeneration and tubular cell necrosis as evident by PAS staining. Cisplatin induced kidney specific mitochondrial oxidative stress, impaired activities of mitochondrial electron transport chain enzyme complexes, impaired anti-oxidant defense enzyme activities such as glutathione peroxidase (GPX) and manganese superoxide dismutase (MnSOD) in mitochondria, inflammation (tumor necrosis factor α and interleukin 1β), increased accumulation of NF-κB in nuclear fraction, p53 induction, and apoptotic cell death (caspase 3 activity and DNA fragmentation). Treatment of mice with EGCG markedly attenuated cisplatin induced mitochondrial oxidative/nitrative stress, mitochondrial damages to electron transport chain activities and antioxidant defense enzyme activities in mitochondria. These mitochondrial modulations by EGCG led to protection mechanism against cisplatin induced inflammation and apoptotic cell death in mice kidney. As a result, EGCG improved renal function in cisplatin mediated kidney damage. In addition to that, EGCG attenuated cisplatin induced apoptotic cell death and mitochondrial reactive oxygen species (ROS) generation in human kidney tubular cell line HK-2. Thus, our data suggest that EGCG may represent new promising adjunct candidate for cisplatin.

The Green Tea Polyphenol(—)-epigallocatechin-3-gallate and its beneficial roles in chronic kidney disease

“…In a mouse model of cisplatin nephrotoxicity, EGCG ameliorate cisplatin induced apoptosis by modulating death of receptor Fas, Bax, and Bcl-2 [47] . In addition to that, EGCG attenuated cisplatin-induced apoptotic cell death and mitochondrial ROS generation in human kidney tubular cell line HK-2 [37] . These findings suggest that EGCG can ameliorate CP-induced apoptosis in the kidney by regulating the ER stress pathway and the mitochondrial pathway.…”

“…It has been the most common cause of ESRD in children. Several groups have reported a reduction of serum creatinine on animal models of obstructive nephropathy by EGCG treatment [37] . To explain the mechanism of action, it has been proposed that EGCG regulates NF-κB activation and induces Nrf2 nuclear translocation [13,38,39] .…”

“…Chen et al showed that EGCG decreased p-ERK, GRP78, caspase-12 of kidney, as ER stress-related markers via inhibition of ER stress-induced apoptosis [46] . Second, a recent study has examined the effect of protection again cisplatin induced renal injury by EGCG through mitochondrial protection by improving mitochondrial electron chain complexes, mitochondrial antioxidant function in enzymes MnSOD and GPX, and improving cisplatin-induced mitochondrial oxidative/nitrative damage and anti-inflammatory effect [37] . In a mouse model of cisplatin nephrotoxicity, EGCG ameliorate cisplatin induced apoptosis by modulating death of receptor Fas, Bax, and Bcl-2 [47] .…”

Renoprotective Effects of Fermented Black Ginseng through Ameliorating Oxidative Stress Associated with Cisplatin-Induced Acute Nephrotoxicity in Mice

“…However, BUN and creatinine levels both WG and FBG were decreased significantly. Herein, pretreatment with WG and FBG attenuated cisplatin-induced renal dysfunction as demonstrated by normalization of BUN and creatinine level compared to cisplatin-control mice [27][28][29][30].…”

“…Accordingly, nephrotoxicity by cisplatin is characterized by renal electrolyte disturbances and by acute fall in glomerular filtration rate (GFR) [27,28]. Cisplatin teatment was found to cause diffuse tubular necrosis and desquamation and parenchyma degeneration in the cortex [29].…”