Part Two The Effect Of Polyphenols On Kidney Disease: Targeting Mitochondria

Antioxidants and Kidney Diseases

1. Caffeic Acid Phenethyl Ester

Caffeic acid phenethyl ester (CAPE) is a natural phenolic compound possessing anti-inflammatory, antioxidant, and immunomodulatory effects [124]. CAPE exhibits a strong antioxidant potential by scavenging free radicals and facilitating oxidative homeostasis [125]. Further, CAPE improved the OXPHOS of mitochondria through the complex-I-dependent substrate(s) glutamate/malate [69]. It was later shown that CAPE pre-treatment protected complex II (SDH) activity and inhibited ROS formation at Complex II F [68]. CAPE reduced Fe3+ (oxidized form of cytochrome C) into Fe2+, inhibiting the release of cytochrome C to cytosol and apoptosis. This protection decreased MDA and xanthine oxidase (XO) while increasing the antioxidant enzyme GSH [68]. Therefore, CAPE inhibited lipid peroxidation in renal tissues [126]. Further, CAPE pre-treatment ameliorated mitochondrial swelling and dissipation of membrane potential following renal toxicity by cadmium [127]. Özeren et al. [128] showed that CAPE prevented kidney ischemia/reperfusion injury by inhibiting lipid peroxidation and improving mitochondrial Ca2+ uptake, resulting in improved mitochondrial energy metabolism [69]. Furthermore, CAPE treatment also boosted levels of NO from endothelial cells, thus preventing pathological damage in ischemia [129]. Consequently, CAPE increased mitochondrial function to uptake calcium and boost OXPHOS [69,129]. Lastly, CAPE was able to lower oxidative stress, increase antioxidant enzyme activity and GSH content, and inhibit MPT pore opening, resulting in improved renal health [130]. Additionally, CAPE blocked ROS production and augmented the activity of antioxidant enzymes, such as SOD and CAT [126]. Since CAPE exhibits potent antioxidant, anti-inflammatory, and mitochondrial protective effects in kidney cells and tissues, this promotes CAPE as a promising new therapeutic agent that has the potential to protect the kidney from damage [126].

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2. Curcumin

Curcumin is a natural polyphenol product derived from the rhizome of the Curcuma longa, exerting anti-inflammatory, antioxidative, anti-tumor, and anti-fibrotic effects [131]. The presence of conjugated double bonds in the curcumin structure allows it to donate an electron and scavenge ROS [132]. Curcumin has shown a protective effect in kidney damage models via its antioxidant activity, leading to the preservation of mitochondrial function [133]. Further, curcumin prevented mitochondrial dysfunction by protecting the mitochondrial respiratory complexes [134]. Some drugs, including gentamycin, reduce the activity of complexes I, II, and IV [134]. The complexes I and IV concentration and activities were recovered through curcumin treatment [134]. Consequently, the phosphorylation efficiency (Adenosine diphosphate (ADP)/Oxygen) ratio in mitochondria oxidizing malate/glutamate and uncoupled respiration was recovered and redox homeostasis was maintained to prevent mitochondrial dysfunction. Curcumin suppresses TNF-α-mediated NF-κB activity in the development of chronic renal failure and inflammation [135,136]. Further, curcumin reduced interferon-gamma (IFNγ) expression but increased IL-10 levels in the renal ischemia/reperfusion model [137].

Curcumin also exhibited protective impacts against various nephrotoxic agents, such as cisplatin, gentamicin, and cadmium [138]. Particularly, curcumin treatment increased the PGC-1α levels and TFAM expression in nephrotoxicity-induced AKI [139,140]. Curcumin also protected the kidneys from oxidative stress in cisplatin-induced nephrotoxicity [141]. For example, curcumin attenuated oxidative stress and lipid peroxidation by scavenging ROS, restoring manganese superoxide dismutase (MnSOD) activity, enhancing glutathione s transferase (GST) activity, and modulating the GSH levels in kidney mitochondria [142]. Mechanistically, curcumin protected against cisplatin-induced oxidative damage by activating transcription factor EB (TFEB), leading to the regulation of autophagy and decreased levels of ROS after elimination of damaged mitochondria [143]. Moreover, curcumin was also able to restore the imbalance of mitochondrial dynamics in cisplatin nephrotoxicity through attenuation of Fis1 levels and restoring OPA1 levels [144]. Curcumin significantly regulated SIRT3, leading to mitochondrial integrity, a decrease in mitochondrial fission, and improved mitochondrial fusion. SIRT3 upregulation by curcumin also reduced dynamin-related protein 1 (DRP1) levels and prevented depolarization of the mitochondrial membrane in nephrotoxicity with cisplatin [142,145]. Further, curcumin treatment showed a higher number of normal-structure mitochondria and lower swollen mitochondria in gentamicin-induced kidney damage, owing to its ability to recover oxygen consumption of mitochondria [134]. Additionally, curcumin also ameliorated the MPT pore opening and protected them from detrimental effects by preserving mitochondrial integrity [134]. Curcumin also showed protective effects in rats with a renal interstitial fibrosis model. In this study, curcumin inhibited the PI3K/Akt mammalian target of the rapamycin (mTOR) signaling pathway activation and upregulated essential proteins, mediating autophagosome formation. This led to suppressing the inflammatory response and mitochondrial dysfunction development [131]. Furthermore, the ability of curcumin to boost mitochondrial biogenesis warrants its exploration and use for renal disease [146].

3. Quercetin

Quercetin, a natural flavonoid abundant in fruits, vegetables, and leaves, is a potent antioxidant, which alleviates cell senescence by reducing oxidative stress [107,147]. Quercetin alleviates oxidative stress, prevents kidney damage, and inhibits renal inflammation in animal models of diabetic nephropathy [148]. Further, quercetin treatment prevented structural and functional damage to renal tissue and suppressed oxidative stress in rats with tubulointerstitial necrosis and cadmium nephrotoxicity [149]. Recently, it was found that quercetin had chemo-protective and anti-apoptotic effects as a result of elevated expression of p53, p21, and p27 and lowered Bax expression in vitro [150]. Quercetin chelated metal ions, such as iron and copper, which were able to scavenge free radicals in vitro experiments [151]. Quercetin also suppressed NF-κB, lipid peroxidation, and expression of pro-inflammatory matrix metalloproteases, whereas it might elevate nitric oxide levels and the non-enzymatic antioxidant capacity of plasma [107]. Quercetin also ameliorated nephrectomy-induced oxidative stress by increasing GPx and decreasing MDA levels in rats [46,152]. In addition, quercetin restored mitochondrial function and protected against DNA double-strand breaks after doxorubicin treatment in H9c2 cells [153]. It was shown that quercetin could increase the expression of Nrf2 in the nucleus to enhance the encoding of antioxidant enzymes and gene expression of HO-1 in rats with CKD [46]. In renal interstitial fibrosis, quercetin significantly enhanced mitophagy by activating SIRT1 and inducing the PINK1-Parkin signaling pathway [153]. Moreover, a reduction in systolic blood pressure was associated with a reduction in epithelial Na+ channel (ENaCs) expression in the kidneys of hypertensive Dahl salt-sensitive rats treated with quercetin [154,155]. Based on the studies, quercetin can be considered a polyphenol with the ability to lower oxidative stress and apoptosis, while improving mitochondria mitophagy and biogenesis in the kidney.

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4. Resveratrol

Resveratrol is a natural stilbenoid polyphenol found in grapes, blueberries, and peanuts [156]. It exhibits anti-inflammatory, anti-cancer, and anti-aging effects, both in cells and in animals [157]. Further, resveratrol has potential in the treatment of kidney diseases to improve overall health [34]. Studies observed that resveratrol enhanced the NADH entry into electron transport, thus, increasing the NAD+ -NADH ratio, which might influence SIRT1 activity [72,158]. There is ample evidence indicating that resveratrol increased all SIRT1 target proteins, which were critical to mitochondrial function and oxidative stress reduction in kidneys [159]. Resveratrol-induced SIRT1 activity triggered a decrease in fibrosis, mesangial expansion, oxidative stress, and inflammatory cytokine levels, resulting in improved kidney function [160,161]. In the kidneys of SIRT1 KO db/db mice, the expression of pro-inflammatory factors mediated by NF-κB and signal transducer and activator of transcription 3 (STAT3) rose dramatically, supporting resveratrol-induced SIRT1’s crucial role in kidney inflammation [162]. Likewise, resveratrol protected against diabetic kidney disease in db/db mice with type 2 diabetes via an AMPK/SIRT1-independent mechanism [163]. The treatment of db/db mice with 20 mg resveratrol/kg/day for 12 weeks led to a reduction in kidney damage and modification of renal diabetes phenotypes [164]. A recent study revealed that resveratrol was essential in restoring mitochondrial function and biogenesis via SIRT1/PGC-1α activation in the kidneys of diabetic mice [165]. It was shown that activation of SIRT1-dependent pathways by resveratrol attenuated kidney injury by upregulation of mitochondrial biogenesis factors [72]. Further, in chickens that were treated with resveratrol, Nrf2 signaling was activated to reverse renal oxidative damage caused by cadmium injury and activate downstream phase II detoxification factors, such as HO-1, NAD(P)H dehydrogenase quinone 1 (NQO1), and GSTs [82]. Likewise, Kim et al. proved that a reduction in oxidative stress through Nrf2 activation ameliorated renal function, proteinuria, and pathological changes in aging mice [157]. Alternatively, resveratrol treatment prevented a decrease in the activity of complex II and complex IV following hemorrhagic shock, which decreased ROS production and damage in a rat model of kidney disease [72]. Additionally, Hui et al. showed that resveratrol treatment raised MMP and activities of complex I and III; therefore, the production of ATP improved and reduced the generation of ROS in a rat model of CKD [34]. Further, Zhang et al. showed that resveratrol reversed mitochondrial injury, diminished the autophagic vacuole number, and ameliorated mitochondrial fission in chicken kidneys [82]. In addition, by improving mitochondrial elongation, resveratrol facilitated autophagy, suppressed Parkin and PINK1 phosphorylation, and degraded mitochondria that were removed [82]. Generally, these studies suggested that treating renal injuries with resveratrol might attenuate nephrotoxicity, I/R, oxidative stress, and apoptosis while increasing antioxidant enzyme activities. In addition, resveratrol treatment might affect mitochondrial biogenesis and dynamics in kidney diseases to ameliorate mitochondrial dysfunction and metabolic stress.

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5. Catechin

Catechin, as a part of the flavonoid family, is present in plants, fruits, teas, red wine, and cacao [166]. In addition to having antioxidant properties, it also exhibits potent anti-inflammatory properties [167]. Catechin protects the kidneys by scavenging free radicals, inhibiting intracellular ROS, chelating redox-active metals, and enhancing antioxidant defense mechanisms [168,169]. In addition, catechin had the potential to prevent MMP loss and apoptosis by restoring the activity of mitochondrial complex I and ATP synthesis [170]. In SK-N-MC cells, catechin boosted the expression of the anti-apoptotic protein Bcl-2 and inhibited the expression of the apoptotic protein Bax [171,172].

Epigallocatechin gallate (EGCG) is catechin esterified with gallic acid [173]. It is the major polyphenol in green tea with antioxidant activity in reducing mitochondrial oxidative stress [174,175]. It was found that EGCG restored mitochondrial electron transport chain function to normal in mouse kidneys with cisplatin-induced damage [176]. Further, EGCG protected against renal injury caused by cisplatin by favoring mitochondrial antioxidant enzymes, such as MnSOD and GPx, and enhancing the anti-inflammatory effect [177]. Further, EGCG treatment significantly reduced DNA damage caused by p65 and P53 and modulated NF-κB nuclear accumulation in cisplatin nephrotoxicity [176]. In the rat model of obstructive nephropathy, treatment with EGCG inhibited NF-κB activation, while improving the phosphorylated IkappaB (IκB) protein and inducing Nrf2 nuclear translocation [177]. EGCG induced GST, GPx, and HO-1 expression, where they were able to eliminate or inactivate ROS and oxidative stress; thus, it could suppress oxidative stress and acute renal injury [178,179]. In a mouse model of nephrotoxicity, EGCG modulated the receptor Bax, and Bcl-2 attenuated cisplatin-induced apoptosis [180]. Thus, EGCG-induced modulation of NF-κB and Nrf2 is a critical element for oxidative stress and inflammation alleviation in acute kidney damage [177,181]. Furthermore, green tea polyphenols (polyphenol + catechin + EGCG) protected the rat kidneys from the oxidative damage caused by a high-fat diet via a SIRT3/MnSOD pathway mediated by PPARα [182]. It was suggested that green tea polyphenols increased PGC1-α and TFAM axis, mitochondria DNA, OXPHOS proteins, and SIRT1 activity related to a reduction in kidney injury and improvement in renal function after cyclosporine treatment of rats [103]. Eventually, EGCG and catechin could enhance mitochondria function by impacting biogenesis, dynamics, and OXPHOS to prevent or treat kidney diseases.

6. Kaempferol

Kaempferol, a natural flavonoid, is found in tea, vegetables, and fruits, such as broccoli, grapes, kale, tomatoes, and citrus fruits [183,184]. Kaempferol has antioxidant, anti-cancer, and anti-inflammatory effects [97]. It was reported that kaempferol caused a significant decline in MDA levels, an indicator of oxidative stress, cytotoxicity, and renal damage in calcineurin inhibitor-induced renal injury and CKD [185]. In addition, kaempferol could lower lipid peroxidation and improve antioxidant defense activity [186]. Tumor necrosis factor-receptor-associated factor 6 (TRAF6), a transcription factor upstream of NF-κB, is downregulated by kaempferol, reducing renal inflammation and fibrosis in renal tubular epithelial cells [187]. It was shown that pre-treatment of kaempferol reduced pro-inflammatory cytokine release, such as IL-12 and TNF-α, and regulated NF-κB levels by hindering the IkappaB kinase (IKK) phosphorylation and IκBα degradation; thus, it ameliorated the cisplatin-mediated inflammation in mouse kidney proximal tubule epithelial (TKPTS) cells [97]. Furthermore, kaempferol inhibited the p38, ERK, and c-Jun N-terminal kinase (JNK) activation, while augmenting Coenzyme Q (CoQ) biosynthesis and content [97]. Treatment with kaempferol increased GSH and SOD2, while reducing TNF-α and IL-6 in the kidneys of doxorubicin-treated rats [106]. Moreover, treatment and pre-treatment with kaempferol in rats increased nuclear accumulation of Nrf2, which was necessary for mitochondrial biogenesis, in contrast to the cisplatin- and doxorubicin-treated animals [106,180]. In addition, the protective effects of kaempferol against streptozotocin-induced diabetic nephropathy could be attributed to its potent antioxidant effect, mediated by upregulation and activation of Nrf2 [188]. Overall, kaempferol can be a potential therapeutic used in treatment, preventing kidney mitochondria injury because it has anti-inflammatory and antioxidative properties.

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7. Grape Seed Proanthocyanidin

Other plant polyphenols, such as grape seed proanthocyanidin extracts (GSPE), have strong therapeutic characteristics against oxidative stress and inflammatory damage [189,190]. The effects of GSPE on obese rats included the stimulation of energy expenditure, an increase in thermogenic capacity, and inhibiting mitochondrial dysfunction in brown adipose tissue [191]. Rats treated with GSPE had fewer mitochondrial degenerations, stabilized mitochondrial enzymes, and corrected mitochondrial dysfunction in the myocardium and brown adipose tissue [191–193]. GSPE served to reduce proteinuria and podocyte injury as well as nephropathy progression in diabetic rats [194]. Further, the antioxidant capacity of GSPE enhanced the activity of SOD2 and CAT and decreased the levels of MDA and inflammatory cytokines, such as TNF-α and Monocyte chemoattractant protein (MCP1), in renal tissues of diabetic rats [195,196]. Additionally, GSPE was able to restore mitochondrial DNA and increase Nrf1 and TFAM RNA expression, which could suppress renal mitochondrial dysfunction [123]. In addition, GSPE protected diabetic podocytes from injury by restoring phosphor-AMPK, SIRT1, and PGC-1α levels [123]. It was shown that protein SIRT1 was the therapeutic target of GSPE against H2O2 injury. GSPE upregulated the SIRT1 and re-established homeostasis of mitochondrial complexes I, II, III, and IV, enhanced antioxidant enzymes, such as SOD2, whereas it inhibited apoptosis factors, such as BAX and P53, in HEK-293 cells [197]. Further, GSPE increased GSH and TBARS and the protein levels of Nrf2, HO-1, and GST in diabetic kidneys and nephrotoxicity [198,199]. By reducing ROS levels, GSPE protected kidneys from oxidative stress-induced injury [195]. Further, GSPE inhibited NF-κB in I/R injuries in Rats; therefore, it reduced the markers of renal injury and oxidative damage and even inactivated the inflammatory pathway [200]. Thus, GSPE reduced renal damage in rats by activating the Nrf2 signaling pathway, which consequently improved the antioxidant capacity of the tissue [198]. These studies revealed that GSPE might be a safe therapeutic candidate to regulate mitochondrial dysfunction in kidney diseases.

8. Hesperetin

As a natural flavonoid found in citrus plants [201], hesperetin has antioxidant, cardiovascular regulation, and anti-cancer activities [93]. Oxidative stress and ROS generation are significant factors in cisplatin-induced AKI [202]. Hesperetin reduces the renal MDA and NO levels and restores the antioxidant enzyme levels, such as GSH, CAT, GPx, and SOD, to normal levels in rats with nephrotoxicity [93]. It was reported that the levels of MDA and NO in the kidneys were reduced by hesperetin and the levels of antioxidant enzymes, such as GSH, CAT, GPx, and SOD, were restored to normal levels. Hesperetin significantly normalized the elevated level of inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, and, thus, protecting the kidney from inflammatory insult in rats with nephrotoxicity [93,203]. Moreover, hesperetin inhibited the phosphorylation of Akt in diabetic nephropathy, indicating that the PI3K/Akt pathway could be involved in the protective effects of hesperetin [204]. Hesperetin also inhibited JNK, ERK, and p38 phosphorylation, suggesting that it could inhibit cisplatin-induced inflammation [205]. Activating the Nrf2 signaling pathway by hesperetin significantly diminished the oxidative damage of ARPE-19 cells and promoted the SIRT6 expression to protect from I/R injury [206,207]. It was shown that hesperetin could inhibit the apoptosis induced by cisplatin, decrease Bax and caspase-3 expression, and increase Bcl-2 expression [208]. Overall, hesperetin protects against nephrotoxicity and diabetic kidney injury by inhibiting inflammation, oxidative stress, and apoptosis.

9. Ellagic Acid

Ellagic acid is a phenolic acid present in fruits and vegetables, such as raspberries, strawberries, walnuts, grapes, and blackcurrants [209]. The antioxidant effect of ellagic acid leads to scavenging O2·−, OH−, and lipid peroxide, therefore, inhibiting lipid peroxidation and improving the antioxidant status [210]. A study proved that ellagic acid reduced serum MDA levels and increased SOD levels, indicating that it alleviated diabetic nephropathy symptoms by reducing oxidative stress [211,212]. Ellagic acid was also reported to lower TNF-α and IL-1β levels in diabetic nephropathy and nephrotoxicity kidney injury mice, which might be mediated through NF-κB; therefore, ellagic acid could be a potent inhibitor of NF-κB activation [211,213]. Further, ellagic acid reduced cellular membrane damage by scavenging free radicals in rats with nephrotoxicity and nephropathy [90]. This protection was shown by covering depleted levels of SOD, GSH, CAT, and Bcl2 in the kidney, inhibiting caspase-3 activation and increasing the Bcl-2/Bax expression ratio. They found that ellagic acid significantly reduced the mitochondrial ROS content, reversed the swelling of the mitochondrial kidney, and prevented the loss of mitochondria membrane potential. Further, it was suggested that the anti-apoptotic effects of ellagic acid could be attributed to the upregulation of Nrf2 [90,120,214]. Additionally, Nrf2 could suppress inflammation by inhibiting TNF-α and NF-κB in diabetic nephropathy in cell lines, an animal model, or both [215]. It also activated different antioxidant enzymes, such as HO-1, NQO1, GST, and GSH [216,217]. The dysfunction of mesangial cells in diabetic nephropathy might be related to the PI3K/Akt signaling pathway activation inhibited by ellagic acid [218]. Ellagic acid treatment also triggered SIRT1 overexpression in renal tissues, which imparted renal tolerance to oxidative stress [214]. Moreover, ellagic acid-induced SIRT1 expression suppressed p53 and promoted cell survival via the expression of antioxidant enzymes, such as CAT [214]. Overall, these results suggest that ellagic acid decreases renal inflammation and oxidative stress, leading to improved kidney function (Figure 2 ).

Discussion and Perspectives

As discussed above, dysfunctional mitochondrial biogenesis, dynamics, or OXPHOS is a vital underlying factor in renal mitochondrial damage [11]. Although the commonly used drugs, such as cisplatin, gentamycin, cyclosporine A, and doxorubicin, in clinical practice have anticancer, antibiotic, and anti-inflammatory effects, they have irreversible side effects on the kidney [225]. The current literature suggests that mitochondrial dysfunction adversely alters kidney function and worsens complications that may promote complex renal diseases [6]. Renal mitochondrial alterations are associated with cellular damage, oxidative stress, inflammation, and apoptosis [226]. Eventually, the disturbed renal mitochondrial homeostasis leads to CKD, AKI derived from nephrotoxicity and I/R, and nephropathy [11]. Overall, the available studies display the need to target mitochondrial dysfunction to restore kidney function and stimulate renal repair or prevent further damage in renal tissues. Even though defective mitochondria are linked to kidney diseases, the pathogenic relationship and our knowledge of the impact of mitochondrial dysfunction in patients with kidney disease remain uncertain. In animal models of kidney damage, mitochondria-targeting therapeutics have been shown to preserve mitochondrial structures and functions [227]. Indeed, dietary antioxidants, such as vitamins C and E, polyunsaturated fatty acids (PUFA), probiotics, N-Acetylcysteine (NAC), and exercise, may be suitable therapeutics for mitochondrial oxidative damage [12,148]. Polyphenols have shown promising potential in specific kidney injuries and diseases in animal and cell studies [18,228–230]. These mitochondria-targeting antioxidants have been demonstrated to effectively decrease ROS accumulation, inhibit the release of pro-inflammatory cytokines, and kidney injury, and favor mitochondrial biogenesis and kidney function in various renal disease models.

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Primarily, the structure of polyphenols allows them to act as an antioxidant, as they can donate an electron and scavenge ROS to make them stable [68,133]. Moreover, recent research has revealed that polyphenols may have more specific cell signaling mechanisms than general antioxidant actions via complex mitochondria function regulation [231]. Emerging evidence indicates that polyphenols, such as resveratrol, quercetin, curcumin, EGCG, kaempferol, ellagic acid, hesperetin, and GSPE, restore mitochondrial biogenesis by stimulating PGC-1α, NRF1/2, and TFAM to improve kidney function [72,134,139,140,198,199]. On the other hand, the down-regulation of apoptotic proteins and release of cytochrome C by polyphenols, such as catechin, ellagic acid, hesperetin, quercetin, and EGCG, represent an anti-apoptotic mechanism and cytoprotective impacts to prevent kidney injury [90,150,182,208]. Notably, some polyphenols, including curcumin and caffeic acid, can ameliorate the MPT pore opening, consequently preserving mitochondrial integrity [126,134]. Another mitochondrial action restricted to catechin and resveratrol inhibits MMP loss and improves ATP production through mitochondria protein complexes [130,134]. Further, polyphenols, including caffeic acid, curcumin, resveratrol, catechin, EGCG, and GSPE, may directly prevent mitochondrial dysfunction in renal injuries by enhancing the activities of mitochondrial electron transport chain complexes [170,176,197]. In addition to acting as antioxidants, polyphenols’ action includes direct up-regulation of antioxidant defense systems, such as SOD, CAT, GSH, and GPx, whereas they decrease MDA and the pro-inflammatory cytokines, such as IL-12 and TNF- α-modulated NF-κB [96,106,126,137,178,179]. Taken together, polyphenols can regulate the electron transport chain activity, improve oxygen consumption, maintain the mitochondrial membrane, and support ATP generation, probably by scavenging free radicals and inhibiting protein and lipid oxidation in nephrotoxicity, I/R, and nephropathy.

Although polyphenols are natural compounds and present themselves as therapeutic possibilities, more detailed studies on the dose of polyphenols for clinical intervention are recommended. Because most of the studies are based on animals and cells, thus, the safety and effectiveness of polyphenols to restore kidney mitochondria should be examined in humans. Further, pre-treatment of some polyphenols, such as caffeic acid and kaempferol, diminished the treatment duration of kidney disease, particularly nephrotoxicity [68,97]. Therefore, further investigations are required to elucidate the exact effect of pre-treatment polyphenols as a prevention agent against kidney disease. It is necessary to analyze whether polyphenols alter mitochondrial dysfunction in kidney disease compared to standard medicine; hence, they can be used as an alternative treatment compared to chemical medicine with more minor side effects. Further, it is necessary to observe interactions between clinically used medicine and polyphenols to address the safety aspects of pharmacology. There is also a lack of data to present the impact of fruits, vegetables, cereals, nuts, and plant consumption on kidney health and mitochondria function. Further, the production of foods rich in polyphenols, food fortification, and polyphenol supplementation plays a significant role in the pharmaceutical use of this strategy. Accordingly, extensive studies on the design of new dietary patterns should be carried out.

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Fatemeh Ashkar, Khushwant S. Bhullar, and Jianping Wu.

Department of Agricultural Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2R3, Canada; fashkar@ualberta.ca (F.A.); bhullar@ualberta.ca (K.S.B.)