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

Immune-mediated renal injury

GN, which accounts for 10—0% of the total incident cases of ESRD, is associated with increased morbidity and mortality. There are various types of GN that are classified based on the type of mechanisms and section of the glomeruli that are affected. The pathogenesis involved in GN can be considered reverently immune mediated, including both cellular (e.g., neutrophils, monocytes) and humoral (e.g., complement) mediated immunity. Among them, antiglomerular basement membrane glomerulonephritis (anti-GBM-GN) is one of the most severe forms of immune-mediated GN, which is directed against an antigen intrinsic to the alpha-3 chain of type IV collagen in the GBM, thereby resulting in rapidly progressive GN, which is typically associated with crescent formation^{[18, 19]}. The contemporary treatment based upon the use of corticosteroids and/or immunosuppressive drugs has given excellent results in improving the survival of both the patient and the kidney; however, this treatment is accompanied by many side effects. Thus, the rationale for an etiological treatment is still lacking.

EGCG are potent anti-inflammatory and antioxidant agents. Recently, it has attracted considerable attention because of its potential role in the pathogenesis of immune-mediated renal injury by targeting multiple signaling and inflammatory pathways. A first study was performed on a murine model of anti-GBM-GN to test whether the anti-inflammatory and antioxidant properties of EGCG favorably affect the course of immune-mediated GN. Pretreatment with EGCG leads to an unequivocal improvement in histological findings and a significant reduction in proteinuria and serum creatinine^[20]. The detailed mechanism is likely to be involved in the decreased oxidative stress and inflammation due to the EGCG treatment. Lower levels of oxidative stress markers MDA and H₂O₂was observed in kidney and urine. Also there was mild focus of NF-ϰB and its downstream gene expression by EGCG^{[21, 22]}. Additionally, ERK1 /2 activation, phosphatidylinositol 3-kinase/Akt, and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is also involved in EGCG^[23]. The latest research demonstrated improvements in renal function and histology and found to be accompanied by the restoration of Nrf2 signaling on experimental crescentic GN induced in 129/svJ mice, as shown by increased nuclear translocation of Nrf2, reduced p-Akt, p-JNK, p-ERK1/2, and p-P38 expressing as well as restoration of PPARγ and SIRT1 levels^[24]. Furthermore, Tsai et al. found that EGCG has prophylactic effects on lupus nephritis in these mice that are highly associated with its effects of enhancing the Nrf2 antioxidant signaling pathway, decreasing renal NLRP3 inflammasome activation, and increasing systemic Treg cell activity^{[22, 25]}. Also, Peairs et al. showed that EGCG inhibits the immune-stimulated PI3K/Akt/mammalian target of rapamycin (mTOR) pathway and blocked LPS/ IFN-γ-induced inflammatory mediator production (iNOS expression, supernatant NO, and interleukin-6) in MRL/ lpr mouse mesangial cells^[26]. Thus, these observations demonstrate the potential utility of EGCG as a therapeutic agent for regulating inflammation and controlling GN or other autoimmune disease.

Diabetic nephropathy

Diabetic nephropathy is one of the most serious complications in diabetes mellitus and has been the most common cause of ESRD^[27]. Various pathways are activated within the diabetic kidney, such as increasing oxidative stress, polyol formation, and AGE accumulation, further stimulating intracellular secondary messengers such as proteinkinase C, mitogen-activated protein kinase, and NF-ϰB, eventually resulting in increasing proteinuria, glomerular sclerosis, and tubulointerstitial fibrosis^{[28, 29]}. Therefore, therapeutic strategies targeting the management and prevention of diabetic nephropathy include agents for controlling hyperglycemia, glucose-derived oxidative stress, and renal damage^[30].

Due to the dominant role of antioxidant and antiglycation properties, EGCG are increasingly being investigated in diabetic nephropathy^{[31, 32]}. In a study performed on streptozotocin-induced diabetic rats fed with diet enriched with EGCG for 50 days, it has been shown that EGCG reduced the level of mRNAs for glyconeogenesis enzymes, suppressed hyperglycemia, proteinuria, and lipid peroxidation in diabetic nephropathy^[33]. In vivo studies from Chen et al. showed that oral administration of a 1:1 mixture of EGCG and Amla extract (AE) for 3 months significantly improved antioxidant defense as well as diabetic and atherogenic indices in uremic patients with diabetes, without significant changes in hepatic or renal function^[34]. One hypothesis to explain these properties is EGCG reduced renal AGE accumulation and its related protein expression in the kidney cortex, which might contribute to alleviating renal damage. Moreover, Cai et al. indicated that carbonyl stress mediated the formation of ubiquitinated, modified protein aggregation is essential in the early development of diabetic nephropathy, while methylated derivative EGCG, which is more stable and efficient than EGCG, could decrease the accumulation of p62, the antiparallel b-sheet/aggregatedstrands, and increase the a-helix content in a diabetic kidney^[35]. Another in vitrostudy conducted on AGE-treated human kidney cells demonstrated that EGCG increased superoxide dismutase levels, decreased inflammation and apoptosis through inhibition of RAGE up-regulation, and NF-ϰB pathway activation^[36]. These studies suggest that dietary supplementation with EGCG could potentially contribute to nutritional strategies and is a safe and effective treatment for the prevention and treatment of DN.

Other related nephropathy

Obstructive nephropathy refers to the presence of structural or functional changes in the urinary tract that impede the normal flow of urine. 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]. In UUO C57BL/6 mice models, it has been found that treatment with 50 mg/ kg EGCG(I.P.) for 14 days inhibits NF-ϰB activation and favored a significant increase in the phosphorylated IϰB protein. The phenomenon of Nrf2 nuclear translocation was also observed in a study conducted on a rat model of obstructive nephropathy. EGCG treatment suppressed oxidative stress and acute renal damage in a dose-dependent manner due to induced expression of glutathione S-transferase, glutathione peroxidase, γ-GCS, and heme 〇xygenase-1(HO-1), which are involved in the elimination or inactivation of ROS and oxidative stress^[38]. These results indicate that EGCG is able to block NF-ϰB signaling pathway, facilitate the release of Nrf2 for nuclear translocation, and finally induce expression of some representative antioxidant enzymes in renal tissue.

Cisplatin (CP) is a commonly used anticancer drug, but its notable side effect of nephrotoxicity limits its use in clinic^[40]. As previously described, cisplatin-induced nephrotoxicity is associated with increased oxidative stress, inflammatory cytokines, and finally result in apoptosis. Several studies have shown that EGCG attenuated the CP-induced apoptosis in animal models and may represent new promising adjunct candidate for cisplatin^[41-44]. The details of EGCG regulate the CP-induced apoptosis is complex and involves multiple mechanisms. First, the imbalance in ER homeostasis, as multifunctional organelle, caused disturbance of calcium homeostasis, glucose deprivation, increasing of ROS formation and oxidative stress induction^[45]. 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]. In addition to that, EGCG attenuated cisplatin-induced apoptotic cell death and mitochondrial ROS generation in human kianey 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.

Source of Foundation

This work was partially sponsored by the Natural Science Foundation of China (No. 81270136, No. 81500508, No. 81671897), Shanghai PujiangProgram (No. 15PJ1406800).