Oxidative stress arises in the cells owing to an imbalance between production and accumulation of ROS, and subsequent inability to detoxify these reactive products (Figure 2) [40,41,42]. ROS is generated in the cells during the normal process of metabolism. Although optimum ROS level helps cell metabolism by cell-to-cell interactions, elevated ROS can cause extreme damage to cells and tissues [43]. The antioxidative defense mechanism of cells combined with an exogenous source of antioxidants is the key to minimizing the damages occurred by oxidative stress. Mangiferin, the natural bioactive compound has already been proven to have antioxidant properties. It may maintain a proper balance between ROS and antioxidants by reducing the level of intracellular ROS. It increases antioxidant activities in the kidney tissues, and subsequently stabilizes superoxide dismutase (SOD) activities, decreases uric acid synthesis, and improves antioxidant effects in mice and rats (Table 1).

Cisplatin (cis-diamminedichloroplatinum II), is an anticancer drug that acts against several types of cancers by increasing intracellular ROS levels leading to oxidative stress, and reducing the antioxidant enzyme activities in the kidney epithelial (NKE) cells [20]. Importantly, mangiferin treatment reduces the kidney ROS levels, oxidative stress marker specifically MDA, and enhanced the antioxidant enzyme activities namely SOD, catalase, glutathione s-transferase (GST), glutathione peroxidase (GPx), and glutathione reductase (GR) are responsible for the degradation of ROS in the renal tissues both in vitro (NKE cells) [20] and in vivo (mice and rats) [20,21].

Several other drugs/chemical compounds cause oxidative damage by increasing ROS levels. Streptozotocin (STZ), a well-known poisonous substance forms ROS and MDA, resulting in induction of oxidative stress and reducing the levels of antioxidants [44]. Interestingly, mangiferin increased antioxidant enzymes as well as reduced ROS and MDA in STZ-induced diabetic mice and rats [7,22,23,24,25,26,27]. In diabetes, advance glycation end product (AGE) and xanthin oxidase plays an important role in inducing ROS; however, mangiferin treatment suppressed AGE generation and inhibited the activities of xanthin oxidase [22], indicating that mangiferin has the potential to reduce the levels of ROS in diabetic patients.

Mangiferin reduces the damage of antioxidants in lipopolysaccharide (LPS)-induced sepsis, thus, recovering sepsis-associated organ impairment [28] and increases antioxidant biomarkers in mouse kidney cells [29]. Besides, it has also been reported that mangiferin reduces intracellular MDA levels by acting as an effective ROS scavenger. Consistently, mangiferin ameliorated the oxidative stress in animal models with different ROS inducers namely uric acid, osteopontin, tert-Butylhydroperoxide (tBHP) and D(+)galactosamine (DGal) [30,31,32,33,34,35] as well as in different kidney cells [37,38,39], as briefly described in Table 1 and Table 2. Collectively, all these data from in vivo and in vitro studies indicated that mangiferin could be a potent therapeutic agent to combat oxidative stress in kidney diseases.

Renal inflammation is initiated by several factors including immune-mediated inflammatory mediators and a subsequent renal dysfunction or nephrotoxicity (Figure 3) [45,46,47,48,49]. Moreover, increased uric acid triggers renal inflammation through the c-Jun N-terminal kinases (JNK) signaling pathway and nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein (NLRP) 3 inflammasome. NLRP3 inflammasome stimulates pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 production and excretion, thus promoting renal injuries and disease in mice such as hyperuricemic nephropathy (HN) [30]. In connection with these, recent studies demonstrated the anti-inflammatory effects of mangiferin in kidney tissues and cells (Table 1 and Table 2). Mechanistically, mangiferin shows its anti-inflammatory effects by inhibiting the activation of both the JNK pathway and NLRP3 inflammasome and minimizing urate [29]. It has also demonstrated that mangiferin treatment preserved the glomerular and tubular structures of kidneys in mice [30]. Cisplatin manifests nephrotoxicity in the liver with deleterious effects in the renal tissues. Cisplatin exposure escalates proinflammatory cytokines (tumor necrosis factor-α; TNF-α, IL-1β, IL-6, IL-10) and nuclear factor-kappa β (NF-κB) in the nuclear fraction of the renal tissue in rats and mice; however, mangiferin treatment attenuated the level of all these cytokines [20,21].

Studies demonstrated that high mobility group box 1 (HMGB1), a protein that binds to toll-like receptors (TLR), activates NF-κB inflammatory signaling pathways inducing the release of inflammatory factors; hence, it contributes to an inflammatory storm in LPS-treated mice, and interestingly, mangiferin prevented the activation of this signaling pathway [28]. Moreover, simultaneous administration of mangiferin reduced cisplatin-instigated nephrotoxicity in vitro and in vivo by preventing the nuclear translocation of NF-κB and proinflammatory cytokines. Blocking NF-κB pathway by mangiferin defeats the NF-κB cascade pathway of inflammation in rats and mice [20,21]. In contrast, tBHP instigated inflammation [34], as well as STZ induced-diabetic nephropathy (DN) [7,22,23,24,25,26,27] were ameliorated by mangiferin. Moreover, DGal advances inflammation by prompting NF-κB and TNFα in rats in renal tissue, and osteopontin (OPN), a proinflammatory cytokine, assists in inflammatory gene expression. Mangiferin preserves renal function appositely against NLRP3 inflammasome [33] and lessens inflammation by obstructing DGal [35] and OPN [33]. In diabetic nephropathy, high glucose generates an inflammatory response characterized by activating the NF-κB pathway, TNF-α, and IL-1β in the renal tissue of diabetic rats, and mangiferin was able to reduce the burden of inflammation in DN [39]. Moreover, mangiferin inhibits renal ischemia-reperfusion damages by blocking inflammatory agents [36] and preserves renal function against cadmium-induced eukaryotic cell death via the NF-κB signaling pathways [38]. All data suggest that mangiferin has the ability to combat inflammation in the kidneys.

Persistent accumulation of extracellular matrix (ECM) in the renal tissue causes kidney fibrosis. ROS helps to intensify the accumulation of ECM by inducing transforming growth factor (TGF)-β1, which is evident in the in vivo mice models [7,50,51,52]. Cellular ROS also leads to activate fibrotic factors such as fibronectin (FN), α-smooth muscle actin (α-SMA), and collagen I (Col I) (Figure 4). FN is a non-collagenous glycoprotein present in ECM and basement membrane, which helps cell adhesion and regulates cell polarity, differentiation, and enlargement, and mangiferin prevents to activate FN [7]. The active protein kinase C beta (PKCβ) pathway contributes to renal fibrosis in hyperuricemia boosted mice [30]. PKC is a family of enzyme threonine kinases along with 12 isoforms. Activation of PKC isoforms enhances the vasoendothelial growth factor (VEGF), leading to Col IV deposition and mesangial growth in rats [23]. OPN is known as ECM protein, and pro-fibrotic adhesion compound induces renal disease tubulointerstitial fibrosis. OPN can act as a mediator for fibrotic changes related to glomerulosclerosis and interstitial fibrosis, however, mangiferin treatment attenuated the development of these pathological changes in kidneys [33].

Mangiferin may act as a new therapeutic agent against chronic fibrotic kidney diseases such as HN and DN [32]. Treatment with mangiferin impedes the expression of FN in hyperuricemic nephropathy in mice [30]. Evidence shows that mangiferin administration effectively shows anti-fibrotic effects against renal interstitial fibrosis by decreasing TGF-β1-induced elevation of Col I, FN, and α-SMA and by inhibiting glomerular ECM development, accumulation, reducing glomerular basement membrane thickness, as well as mesangial cell growth in STZ, instigated diabetic mice [7]. Taken together, mangiferin could become a potential therapeutic option to inhibit the fibrotic changes in kidneys.

ROS activates mitogen-activated protein kinases (MAPK) pathways along with JNK, p38 kinases, and extracellular signal-regulated kinases (ERK) by inducing cellular stress in rats [7]. The downstream pathway of MAPK involves three essential serine kinase proteins, including JNK, ERK1/2, and p38. These proteins assist in apoptosis and cell death. Importantly, mangiferin treatment reduced ROS generation and subsequently alter the MAPK pathway [21]. In contrast, proapoptotic (Bax, Bad, etc.) and anti-apoptotic (Bcl-2, Bcl-xl) proteins are entangled in apoptosis in STZ persuaded diabetic rats, which is attenuated by mangiferin treatment [22]. TNF-α activates caspase 8, while caspase 8 and 3 play a significant role to ensure programmed cell death that is apoptosis. Also, phosphorylation of JNK protein executes apoptosis and mangiferin treatment successfully prevents apoptosis in kidney tissues [22]. DGal, a toxic component, upregulates caspase 3/9 and changes the reciprocal regulation of Bcl-2 family proteins and these proteins govern permeabilization of outer membrane mitochondria. Bax and Bad proteins initiate apoptosis, release cytochrome c into the cytosol, and gradually activate the pro-apoptotic caspase cascade. Anti-apoptotic proteins Bcl-2 and Bcl-xL suppress Bax and Bak oligomer [35]. AMP-activated protein kinase (AMPK), a serine protein kinase that responds to cellular stress is activated when cellular energy is insufficient, thus inhibits mammalian target of rapamycin complex (mTOR) activity and increases autophagy. Autophagy refers to the degradation associated with the clearance of injured proteins and organelles initiated by activating the unc-51-like kinase 1 (ULK1) complex. ULK1 complex is prevented by mTOR activities AMPK phosphorylation decreases mTOR phosphorylation and manifests a nephroprotective effect by regulating MAPK. Mangiferin treatment was proven to have beneficial effects on these molecular machineries [24]. Moreover, pre-treatment with mangiferin exerts uricosuric action in hyperuricemic rats associated with obstruction of urate reabsorption through down-regulation of the mRNA and protein expressions of urate transporters in renal cells [32]. It also damages apoptotic proteins such as p53 and Nrf-2 related signaling cascades, reduces caspase and mitochondrial dysfunction [20,22]. Furthermore, it rehabilitates the altered Bax/Bcl-2 ratio by reducing mitochondrial dysfunction, releasing cytochrome C in the cytoplasm from the mitochondria [30], and diminishing Bax proteins in DGal revealed rats [35]. Mangiferin exerts beneficial effects on these different molecular cascades.

A mangiferin aglycon derivative J99745 has been used as a potent xanthine oxidase (XOD) inhibitor in vitro study. J99745 exerts urate-lowering effect by inhibiting XOD activity and renal urate transporter 1 (URAT1) expression [31].