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

Abstract

Mitochondrial function, including oxidative phosphorylation (OXPHOS), mitochondrial biogenesis, and mitochondria dynamics, are essential for the maintenance of renal health. Through modulation of mitochondrial function, the kidneys can sustain or recover acute kidney injury (AKI), chronic kidney disease (CKD), nephrotoxicity, nephropathy, and ischemia perfusion. Therapeutic improvement in mitochondrial function in the kidneys is related to the regulation of adenosine triphosphate (ATP) production, free radicals scavenging, decline in apoptosis, and inflammation. Dietary antioxidants, notably polyphenols present in fruits, vegetables, and plants, have attracted attention as effective dietary and pharmacological interventions. Considerable evidence shows that polyphenols protect against mitochondrial damage in different experimental models of kidney disease. Mechanistically, polyphenols regulate mitochondrial redox status, apoptosis, and multiple intercellular signaling pathways. Therefore, this review attempts to focus on the role of polyphenols in the prevention or treatment of kidney disease and explore the molecular mechanisms associated with their pharmacological activity.

Keywords

kidney; mitochondrial function; polyphenols; acute and chronic renal diseases.

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Introduction

Kidneys are one of the most energy-demanding organs and play a vital physiological role in the maintenance of salt and water homeostasis [1]. Kidneys receive approximately 25% of the cardiac output and are responsible for the regulation of blood pressure and continuous blood filtration [2]. Physiologically, kidneys consume about 7% of the total oxygen available for overall human function, indicating a significant role of mitochondria in their physiology [2]. Mitochondria are abundant in metabolically active organs, including kidneys, especially in the renal tubule cells [3,4]. Indeed, the kidney is a metabolically active organ containing more mitochondria per weight than any other human organ [5,6]. Acute and chronic kidney diseases, such as renal ischemia, toxicity, and acute injury, include underlying mitochondrial dysfunction [7–9]. Research has established links between both acute and chronic kidney diseases with impaired mitochondrial biogenesis, OXPHOS, and mitochondria mitophagy [10]. Mitochondrial dysfunction in kidneys is also linked to inflammation, apoptosis, and tissue injury, thus, contributing to mortality and morbidity rates [11]. Studies have shown that dietary patterns and dietetic components could modulate renal function and disease [12,13]. A diet rich in plants, vegetables, and fruits is related to a lower incidence of chronic diseases, such as cardiovascular disease, cancers, type 2 diabetes, and kidney disease(s) [14,15]. These biological functionalities are associated with the presence of active antioxidants, particularly polyphenols [15]. ‘Polyphenol’ is not a strict chemical term and is used to refer to flavonoids, tannins, and phenolic acids and their various chemically modified or polymerized derivatives [16]. Over the last two decades, multiple polyphenols have attracted attention as nephroprotective agents, particularly owing to their ability to maintain oxidative homeostasis and activate cytoprotective signaling in vivo (Figure 1) [17]. Recent studies have shown the therapeutic effects of bioactive compounds and their beneficial health effects; however, little effort has been put into summarizing the impact of polyphenol interventions on mitochondrial dysfunction in various renal diseases [12,18,19]. This literature review attempts to focus on the role of polyphenols in the prevention and/or treatment of kidney disease and explore the cellular mechanisms associated with their pharmacological activity. We mainly focus on preclinical studies, both cellular and animal, that displayed the ability of polyphenols to decrease physiological complications and enhance mitochondrial function.

Bioavailability of Polyphenols

Recent studies have reinforced the health-promoting evidence of polyphenols based on diverse experimental models [20,21]. However, their chief problems are their low bioavailability and rapid metabolism [22]. Therefore, the bioavailability of polyphenols has been considered a significant limitation for their clinical evaluation and translations.

After polyphenol administration, oxidation, reduction, hydrolysis, and conjugation cause the production of different water-soluble conjugate metabolites, which can pass the enteric barrier for further distribution to organs [20,23]. These processes are mediated by lactase phlorizin hydrolase (LPH) and cytosolic β-glucosidase (CBG) [24]. Multidrug-resistance-associated proteins (MRP-1 and MRP-2) also play essential roles in polyphenol bioavailability and tissue accumulation [25]. During intestinal transit, MRP-2 on the apical surface of cells transports intracellular polyphenols to the lumen of the intestine. MRP-1, located in the vascular pole of enterocytes, promotes polyphenol passage from the enterocyte into the bloodstream [24]. MRP-3 and the glucose transporter 2 (GLUT2) efflux polyphenol metabolites from the enterocyte's basolateral membrane to the portal circulation and reach the liver [24]. It is reported that small intestines can only absorb about 5–10% of the total polyphenol intake after deglycosylation [26]. About 90–95% of unmodified polyphenols and the conjugated forms pass through the intestinal tract to the large intestine for gut microbiota action. Gut microbiota can produce various metabolites to exert physiological impacts [27].

Despite the relatively few studies demonstrating lower mitochondrial uptake of polyphenols, their lipophilicity, and pKa make them more suitable for mitochondrial enrichment (28). A recent study showed that polyphenols were more bioavailable and could reach mitochondrial sites of action than previously assumed (29]. The pH value of cells affects the diffusion of polyphenols. Polyphenols are neutral phenols and form phenolate anions in the cytosol (29,30]. Their lipophilicity determines their ability to cross cell membranes and inner- and outer-mitochondrial membranes. Due to their pKa values close to the cytosol's and mitochondria's pH and distribution coefficients, many polyphenols can reach the mitochondrial matrix and release a proton in a relatively basic environment. (29). At that time, phenolate anions move back down the electrochemical gradient to the relatively acidic intermembrane space. Protons are then transported from the inner-mitochondrial membrane to the matrix to regulate the electrochemical gradient (Am) (29,30]. In general, studies have shown that polyphenols are bioavailable and their metabolism via different mechanisms is responsible for their biological activities (31,32].

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Mitochondria and Kidneys

1. Oxidative Phosphorylation (OXPHOS) System

Mitochondria are the central site for over 90% of ATP production in cells [33,34]. ∆Ψm in mitochondria is critical for mitochondrial function and is widely used as an indicator for mitochondrial function and oxidative stress [35]. The overproduction of reactive oxygen species (ROS), primarily superoxide anion (O2·−), during the transfer of electrons to oxygen, and a deficiency in antioxidant enzymes, such as superoxide dismutase (SOD) and glutathione (GSH) [36], leads to oxidative stress, mitochondrial dysfunction, and apoptosis [37]. Because mitochondrial ROS can inhibit multiple signaling pathways and prevent redox-dependent proteins’ proper function and activity, it is reported that mitochondrial ROS could be detrimental to cell survival and the health of a kidney cell [38]. ROS are produced in both the renal cortex and medulla, resulting in altering renal blood flow, inflammation, fibrotic changes, and proteinuria [39].

2. Mitochondrial Biogenesis

Mitochondrial biogenesis is an intricate and adaptive cellular response process [40]. It requires coordinated transcription and replication of mitochondrial DNA accompanied by the synthesis and import of proteins [5]. The mitochondrial biogenesis is regulated by the proliferator-activated receptor-gamma coactivator-1α (PGC-1α) family of transcriptional coactivators [12]. Mitochondrial biogenesis, respiration, fatty acid β-oxidation, and OXPHOS are all controlled by the interaction of PGC1-α with different transcription factors, such as nuclear respiratory factors 1 and 2 (Nrf1/2) and peroxisome proliferator-activated receptors (PPARα) [38]. The PGC-1α transcriptional coactivator is highly expressed in the proximal tubules of the kidney and plays a critical role in tubular homeostasis [11]. AMPactivated protein kinase (AMPK) and family of NAD+ -dependent deacetylases known as Sirtuins (SIRT1–7), including SIRT1, are essential modulators of energy metabolism. AMPK with phosphorylation and SIRT1 through deacetylation can positively regulate PGC-1α [41–43]. Stimulation of PGC-1α through deacetylation or phosphorylation can stimulate the pathway followed by activation of nuclear transcription series factors, such as Nrf1, Nrf2, and transcription factor A mitochondria (TFAM) expression, consequently leading to mitochondria DNA (mtDNA) transcription and replication [44]. Moreover, PGC-1α activation improves the nicotinamide adenine dinucleotide (NAD+ ) biosynthesis, a key molecule critical for oxidative metabolism and cell protection [11]. It is reported that transgenic expression of PGC-1α leads to increased mitochondrial content and expression of mitochondrial genes. Conversely, loss of PGC-1α results in reducing the mitochondrial genes expression and causes mitochondrial dysfunction in mice [38]. There has been widespread evidence of reduced mitochondrial biogenesis as well as low PGC-1α levels in AKI and CKD [45]. Further, the Nrf2 antioxidant pathway was established to cope with CKD-induced oxidative stress in renal cells. Nrf2 is bound to its repressor under normal physiological conditions; under oxidative stress, Nrf2 is rapidly dissociated and translocated to the nucleus, encoding the antioxidant enzyme gene [46]. On the other hand, ROS, oxidative stress, and inflammation suppress the antioxidant potential of renal cells by suppressing the expression of Nrf2 [47]. Cellular homeostasis is integrated with the function of mitochondria and biogenesis. It leads to metabolic syndrome, neurodegenerative diseases, and cancer if the intracellular pathway is malfunctioned [44]. According to the broad involvement of PGC-1α and Nrf1/2 as important factors of mitochondria biogenesis, they can serve as vital pharmacological targets in metabolic diseases.

3. Mitochondrial Dynamics

To maintain cellular homeostasis and mitochondrial function, mitochondrial dynamics, such as division, fusion, and movement, are indispensable [48–50]. There are also fission proteins regulating mitochondrial dynamics, including mitochondrial fission 1 (Fis1), fusion proteins, and optical atrophy (OPA1) [7,51]. For the optimal function of mitochondria, there must be a balance between fission and fusion events, since imbalanced mitochondrial dynamics will eventually result in diseases, such as insulin resistance and type 2 diabetes, hypertension, cardiovascular diseases, and obesity [11,38,52]. Further, kidney disease and impairment are related to increased mitochondrial fragmentation [53]. These findings suggest that balanced mitochondrial fission and fusion are necessary for optimal mitochondrial function in kidney cells.

4. Mitophagy

Mitophagy is the autophagy of accumulated dysfunctional mitochondria modulated by PTEN-induced putative kinase 1 (PINK1)-parkin RBR E3 ubiquitin-protein ligase (PARK2) pathways (a ubiquitin-dependent mechanism) and B-cell lymphoma 2 (Bcl2) interacting protein 3 (a ubiquitin-independent mechanism) [3,54–56]. There is an association between disturbed mitophagy and kidney diseases, such as acute kidney injury, diabetic nephropathy, and glomerulosclerosis [11]. In PINK1 and/or PARK2 knockout models, ROS production, inflammation, mitochondrial fragmentation, and cell apoptosis were enhanced in kidney cells, resulting in severe kidney injury. This suggests that PINK1 and PARK2 pathways act as protective mechanisms in AKI to maintain renal tubular integrity and kidney function [57].

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Kidney and Mitochondria

Chronic and acute kidney injuries are linked with the production of ROS and reactive nitrogen species (RNS) [11]. Oxidative stress in AKI results from sepsis, ischemia-reperfusion injury, exposure to nephrotoxic reagents, and diabetic nephropathy. It was revealed that a balance between fission and fusion tended toward fission, contributing to mitochondrial fragmentation in AKI [58]. As a consequence, fragmentation could be related to the release of apoptotic factors, such as cytochrome C, activation of caspase, and apoptosis [53]. Additionally, AKI in cell and mouse models showed a decrease in mitophagy, ROS production, inflammation, and an increase in mitochondrial damage [59]. Renal fibrosis and, consequently, CKD usually result from repeated or severe AKI [60–62]. Further, CKD may arise from environmental exposure to metal, pesticides, and infectious agents, decreased glomerular filtration rate, and higher urinary albumin excretion [63,64]. Enhanced fragmentation of mitochondria in kidney tubules, reduced mitochondrial biogenesis, loss of mitochondria membrane potential (MMP), drop in ATP generation, and overproduction of mitochondrial ROS were reported in CKD [38,65]. Thus, CKD and AKI might perturb mitochondria biogenesis, dynamics, and mitophagy clearance. The conditions are all likely to lead to an accumulation of inflammatory cytokines, the release of pro-apoptotic factors, and tissue damage [11].

An ischemic/reperfusion (I/R)-injury-induced AKI is a cellular injury that is triggered by a pathological condition that results in blood returning to tissues that have been ischemic [66]. I/R contributes to kidney dysfunction and AKI [67]. It is accompanied by inflammation, ROS and cytokine generation, lipid peroxidation, changes in mitochondrial function, and mitochondria injury [68,69]. I/R could increase the protein levels of pro-inflammatory factors, including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6), and levels of the ROS and malondialdehyde (MDA) while decreasing SOD and GSH [70]. In mitochondria, cytochrome oxidase (complex IV) can catalyze electron transfer from cytochrome C to oxygen to produce a proton gradient for ATP synthesis [71]. ROS and lipid peroxidation products effectively inhibit mitochondrial complex IV activity [36,72], thus, influencing the electron flow across the electron transport chain and ATP production [73]. As a result of lipid peroxidation, different pathways lead to apoptosis and autophagy [74]. In another study, the Nrf2/heme oxygenase-1 (HO-1) signaling pathway decreased renal I/R injury by mediating oxidative stress [75]. Ca2+ at physiological concentrations is an essential regulator of mitochondrial energy metabolism [76]. Ca2+ influx into the mitochondria is a noteworthy factor in triggering mitochondrial ROS production [77]. Overproduction of ROS might result from increased mitochondrial Ca2+ accumulation, leading to inhibition of electron transport and/or an increase in the enzymes responsible for ROS generation [78]. The mitochondrial Ca2+ load reduces the transmembrane potential and opens the mitochondrial permeability transition pore (MPT), damaging mitochondria and mitochondrial respiratory chains and subsequent ROS surge [79]. On the other hand, it was found that ischemic injury decreased the OXPHOS and Ca2+ uptake in kidney mitochondria, which could impact mitochondrial metabolism [69]. These studies demonstrated that I/R-induced inflammation, oxidative stress, and apoptosis might be related to kidney mitochondria. Acute kidney injury resulting from nephrotoxicity could damage mitochondria and, consequently, impair renal functions [80].

Cadmium is a toxic heavy metal, which has extensive nephrotoxic impact [81]. The expression of PGC-1α, Nrf1, SIRT1, and TFAM involved in mitochondrial biogenesis was impaired in cadmium-induced nephrotoxicity [82]. Nephrotoxicity caused mitochondrial fission by inhibiting mitochondrial membrane fusion and activating mitophagy mediated by the PINK/Parkin pathway [83]. Cadmium-induced renal impairment might alter tissue redox status by increasing lipid peroxidation products, such as MDA and nitrite oxide (NO), and decreasing SOD and catalase (CAT) enzymes in the kidneys [84]. This leads to disruption in mitochondria function, mitochondrial membrane potential, and eventually, renal hemostasis [82,85,86].

The antibiotic gentamycin is widely used to treat bacterial infections [87]. Nephrotoxicity caused by gentamycin also triggers ROS production in mitochondria, stimulating the opening of the MPT pore [88]. Thus, the MPT pore opening triggers the release of cytochrome C into cytosol which leads to swelling of mitochondria, activation of caspase cascade, and finally culminates in apoptosis [89]. In addition, the Bcl-2/Bcl-2-associated X (Bax) ratio, which is a vital factor to control cell apoptosis, decreased in the kidney following nephrotoxicity [90].

Anticancer drugs, such as cisplatin, cause DNA crosslinking and apoptosis [91]. Likewise, cisplatin-induced nephrotoxicity elevated protein oxidation and lipid peroxidation in the kidney mitochondria of rats, resulting from increasing ROS production or decreasing antioxidant status [92]. After cisplatin administration, the levels of the lipid peroxidation end-product MDA have significantly increased along with GSH and SOD depletion in rats [93]. The enhanced lipid peroxidation in mitochondria might cause decreased mitochondrial membrane fluidity, an increase in the distribution of negative surface charge, and altered ionic membrane permeability [94]. Cisplatin triggers signaling cascades, such as p53, MAP kinase (MAPK), and nuclear factor kappa B (NF-κB), by ROS formation [95]. Further, cisplatin released pro-inflammatory cytokines, for instance, interleukin 12 (IL-12), TNF-α, and IL-1β to induce kidney damage [96]. Therefore, cisplatin was able to damage the kidney by generating oxidative stress, inflammation, DNA damage, apoptosis, and mitochondrial dysfunction [97].

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Cyclosporine A is an immunosuppressive drug used to treat autoimmune diseases and prevent organ rejection [98]. Studies indicated that cyclosporine A could cause acute and chronic nephrotoxicity by inhibiting mitochondrial respiration and decreasing ATP production in vivo and in vitro [99–102]. Cyclosporine A might suppress mitochondria biogenesis to induce nephrotoxicity [103]. Human kidney proximal tubule epithelial cells treated with cyclosporine A showed increased mitochondrial dysfunction and cellular death induced by H2O2. ROS production during H2O2 injury could activate the p53 pathway. In addition to binding DNA, activated p53 could accumulate in the mitochondrial matrix and trigger necrotic cell death by opening the MPT pore [104].

Doxorubicin, an anticancer agent, is widely used in the treatment of leukemia, breast cancer, and solid tumors [105]. Similar to other nephrotoxic drugs, there was an association between doxorubicin exposure and declining antioxidant parameters, such as glutathione peroxidase (GPx), SOD, and CAT, as well as SIRT1 activity [106,107]. Research showed that doxorubicin elevated thiobarbituric acid reactants (TBARS) and MDA, an indicator of oxidative damage [108]. NF-κB activation plays a critical role in the pathogenesis of doxorubicin-induced renal inflammation [109]. According to this, NF-κB was responsible for inflammatory reactions by mediating TNF-α, IL-1β, and IL-6 expressions in rats treated with doxorubicin [110]. The formation of superoxide radical(s) by doxorubicin exposure led to apoptosis [111,112]. Further, doxorubicin-treated animals showed cell death and apoptosis characterized by upregulation of Bax, down-regulation of Bcl2, increased mitochondrial permeability, and activation of caspase-3 in kidneys [106].

Diabetic nephropathy, a complication of microvascular diabetes, could cause renal disease [113]. Redox changes are caused by persistent hyperglycemia and the accumulation of advanced glycation end products (AGEs) [114]. The resulting chronic inflammatory response leads to aberrant redox changes, albuminuria, proteinuria, glomerulosclerosis, and tubule-interstitial fibrosis [115]. Complications associated with diabetes are caused by ROS production, can damage mitochondrial DNA, and induce cell dysfunction [116,117]. These changes in renal cells, including glomerular endothelial cells, mesangial cells, and renal epithelial cells, disrupt ATP synthesis, cause intracellular calcium imbalances, and contribute to apoptosis and necrosis [118]. Diabetic rats’ kidney tissues showed higher levels of ROS, MDA, TNF-α, IL-6, and NF-κB p65 [119]. Apoptosis was also observed with higher Bax protein and cleaved caspase-3 levels, increased cytochrome c cytoplasmic levels, and Bcl2 down-regulation. In addition, the kidneys of diabetic rats revealed a significant decrease in the mRNA levels and nuclear levels of Nrf2, with a reduction in SOD mRNA levels and SOD and GSH protein levels. This disruption in cellular viability and oxidative homeostasis was possibly backed by hyperglycemia-induced ROS surge and depleted Nrf2 pool [120]. In diabetic nephropathy, oxidative stress might increase GSH degradation or lower innate GSH synthesis. Moreover, ROS also lowers the enzymatic activities of SOD and CAT [121]. Further, free radicals induced during diabetic nephropathy lowered the activity of AMPK and SIRT1, the critical regulators of PGC1α activity and energy metabolism of mitochondria [122]. The injury of the podocyte cells that cover the outer surfaces of glomerular capillaries, related to Nrf1 and mitochondrial dysfunction, contributed to diabetic kidney disease [123]. Studies have also shown that mitochondrial damage contributed to chronic and acute kidney injury as a result of a reduction in mitochondrial DNA, mitochondrial membrane potential, and ATP production along with an increase in inflammation, and apoptosis [65].

References

1. Vart, P.; Grams, M.E. Measuring and Assessing Kidney Function. Semin. Nephrol. 2016, 36, 262–272.

2. Hartogh, D.J.D.; Tsiani, E. Health Benefits of Resveratrol in Kidney Disease: Evidence from In Vitro and In Vivo Studies. Nutrient 2019, 11, 1624.

3. Forbes, J.M. Mitochondria–Power Players in Kidney Function? Trends Endocrinol. Metab. 2016, 27, 441–442.

4. Hoenig, M.P.; Zeidel, M.L. Homeostasis, the Milieu Intérieur, and the Wisdom of the Nephron. Clin. J. Am. Soc. Nephrol. 2014, 9, 1272–1281.

5. Pagliarini, D.J.; Calvo, S.E.; Chang, B.; Sheth, S.A.; Vafai, S.B.; Ong, S.-E.; Walford, G.A.; Sugiana, C.; Boneh, A.; Chen, W.K.; et al. A Mitochondrial Protein Compendium Elucidates Complex I Disease Biology. Cell 2008, 134, 112–123.

6. Bhargava, P.; Schnellmann, R.G. Mitochondrial energetics in the kidney. Nat. Rev. Nephrol. 2017, 13, 629–646.

7. Duann, P.; Lianos, E.A.; Ma, J.; Lin, P.-H. Autophagy, Innate Immunity and Tissue Repair in Acute Kidney Injury. Int. J. Mol. Sci. 2016, 17, 662.

8. Hill, N.R.; Fatoba, S.T.; Oke, J.L.; Hirst, J.A.; O’Callaghan, C.A.; Lasserson, D.S.; Hobbs, F.D.R. Global Prevalence of Chronic Kidney Disease—A Systematic Review and Meta-Analysis. PLoS ONE 2016, 11, e0158765.

9. Lameire, N.H.; Bagga, A.; Cruz, D.; De Maeseneer, J.; Endre, Z.; A Kellum, J.; Liu, K.D.; Mehta, R.L.; Pannu, N.; Van Biesen, W.; et al. Acute kidney injury: An increasing global concern. Lancet 2013, 382, 170–179.

10. Fontecha-Barriuso, M.; Martin-Sanchez, D.; Martinez-Moreno, J.; Monsalve, M.; Ramos, A.; Sanchez-Niño, M.; Ruiz-Ortega, M.; Ortiz, A.; Sanz, A. The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases. Biomolecules 2020, 10, 347.

11. Duann, P.; Lin, P.-H. Mitochondria Damage and Kidney Disease. Mitochondrial Dyn. Cardiovasc. Med. 2017, 982, 529–551.

12. Mafra, D.; Gidlund, E.-K.; Borges, N.A.; Magliano, D.C.; Lindholm, B.; Stenvinkel, P.; Von Walden, F. Bioactive food and exercise in chronic kidney disease: Targeting the mitochondria. Eur. J. Clin. Investig. 2018, 48, e13020.

13. Yi, W.; Xie, X.; Du, M.; Bu, Y.; Wu, N.; Yang, H.; Tian, C.; Xu, F.; Xiang, S.; Zhang, P.; et al. Green Tea Polyphenols Ameliorate the Early Renal Damage Induced by a High-Fat Diet via Ketogenesis/SIRT3 Pathway. Oxidative Med. Cell. Longev. 2017, 2017, 9032792.

14. Boeing, H.; Bechthold, A.; Bub, A.; Ellinger, S.; Haller, D.; Kroke, A.; Leschik-Bonnet, E.; Müller, M.J.; Oberritter, H.; Schulze, M.; et al. Critical review: Vegetables and fruit in the prevention of chronic diseases. Eur. J. Nutr. 2012, 51, 637–663.

15. Mehmood, A.; Zhao, L.; Wang, C.; Nadeem, M.; Raza, A.; Ali, N.; Shah, A.A. Management of hyperuricemia through dietary polyphenols as a natural medicament: A comprehensive review. Crit. Rev. Food Sci. Nutr. 2017, 59, 1433–1455.

16. Williamson, G. The role of polyphenols in modern nutrition. Nutr. Bull. 2017, 42, 226–235.

17. Adekunle, I.A.; Imafidon, C.E.; Oladele, A.A.; Ayoka, A.O. Ginger polyphenols attenuate cyclosporine-induced disturbances in kidney function: Potential application in adjuvant transplant therapy. Pathophysiology 2018, 25, 101–115.

18. Tovar-Palacio, C.; Noriega, L.G.; Mercado, A. Potential of Polyphenols to Restore SIRT1 and NAD+ Metabolism in Renal Disease. Nutrients 2022, 14, 653.

19. Bendokas, V.; Skemiene, K.; Trumbeckaite, S.; Stanys, V.; Passamonti, S.; Borutaite, V.; Liobikas, J. Anthocyanins: From Plant Pigments to Health Benefits at Mitochondrial Level: Reviews; Critical Reviews in Food Science and Nutrition; Taylor & Francis: Philadelphia, PA, USA, 2020; Volume 60.

20. Del Rio, D.; Rodriguez-Mateos, A.; Spencer, J.P.E.; Tognolini, M.; Borges, G.; Crozier, A. Dietary (Poly) phenolics in Human Health: Structures, Bioavailability, and Evidence of Protective Effects Against Chronic Diseases. Antioxid. Redox Signal. 2013, 18, 1818–1892.

21. Teng, H.; Chen, L. Polyphenols and bioavailability: An update. Crit. Rev. Food Sci. Nutr. 2019, 59, 2040–2051.

22. Brglez Mojzer, E.; Knez Hrnˇciˇc, M.; Škerget, M.; Knez, Ž.; Bren, U. Polyphenols: Extraction Methods, Antioxidative Action, Bioavailability and Anticarcinogenic Effects. Molecules 2016, 21, 901.

23. Spencer, J.P.E.; Chowrimootoo, G.; Choudhury, R.; Debnam, E.S.; Srai, S.K.; Rice-Evans, C. The small intestine can both absorb and glucuronidate luminal flavonoids. FEBS Lett. 1999, 458, 224–230.

24. Santhakumar, A.B.; Battino, M.; Alvarez-Suarez, J.M. Dietary polyphenols: Structures, bioavailability and protective effects against atherosclerosis. Food Chem. Toxicol. 2018, 113, 49–65.

25. Leonarduzzi, G.; Testa, G.; Sottero, B.; Gamba, P.; Poli, G. Design and development of nanovehicle-based delivery systems for preventive or therapeutic supplementation with flavonoids. Curr. Med. Chem. 2010, 17, 74–95.

26. Cardona, F.; Andrés-Lacueva, C.; Tulipani, S.; Tinahones, F.J.; Queipo-Ortuño, M.I. Benefits of polyphenols on gut microbiota and implications in human health. J. Nutr. Biochem. 2013, 24, 1415–1422.

27. Bowey, E.; Adlercreutz, H.; Rowland, I. Metabolism of isoflavones and lignans by the gut microflora: A study in germ-free and human flora associated rats. Food Chem. Toxicol. 2003, 41, 631–636.

28. Naven, R.T.; Swiss, R.; Klug-McLeod, J.; Will, Y.; Greene, N. The Development of Structure-Activity Relationships for Mitochondrial Dysfunction: Uncoupling of Oxidative Phosphorylation. Toxicol. Sci. 2012, 131, 271–278.

29. Stevens, J.F.; Revel, J.S.; Maier, C.S. Mitochondria-Centric Review of Polyphenol Bioactivity in Cancer Models. Antioxid. Redox Signal. 2018, 29, 1589–1611.

30. Spycher, S.; Smejtek, P.; Netzeva, T.I.; Escher, B.I. Toward a Class-Independent Quantitative Structure−Activity Relationship Model for Uncouplers of Oxidative Phosphorylation. Chem. Res. Toxicol. 2008, 21, 911–927.

31. Velderrain-Rodríguez, G.R.; Palafox-Carlos, H.; Wall-Medrano, A.; Ayala-Zavala, J.F.; Chen, C.-Y.O.; Robles-Sánchez, M.; Astiazaran-García, H.; Alvarez-Parrilla, E.; González-Aguilar, G.A. Phenolic compounds: Their journey after intake. Food Funct. 2014, 5, 189–197.

32. Hussain, M.B.; Hassan, S.; Waheed, M.; Javed, A.; Farooq, M.A.; Tahir, A. Bioavailability and Metabolic Pathway of Phenolic Compounds. 5. In Plant Physiological Aspects of Phenolic Compounds; Marcos, S.-H., Rosario, G.-M., Mariana, P.-T., Eds.; IntechOpen: Rijeka, Croatia, 2019.

33. Barchiesi, A.; Bazzani, V.; Tolotto, V.; Elancheliyan, P.; Wasilewski, M.; Chacinska, A.; Vascotto, C. Mitochondrial Oxidative Stress Induces Rapid Intermembrane Space/Matrix Translocation of Apurinic/Apyrimidinic Endonuclease 1 Protein through TIM23 Complex. J. Mol. Biol. 2020, 432, 166713.

34. Hui, Y.; Lu, M.; Han, Y.; Zhou, H.; Liu, W.; Li, L.; Jin, R. Resveratrol improves mitochondrial function in the remnant kidney from 5/6 nephrectomized rats. Acta Histochem. 2017, 119, 392–399.

35. Hüttemann, M.; Lee, I.; Pecinova, A.; Pecina, P.; Przyklenk, K.; Doan, J.W. Regulation of oxidative phosphorylation, the mitochondrial membrane potential, and their role in human disease. J. Bioenerg. Biomembr. 2008, 40, 445–456.

36. Angelova, P.R.; Abramov, A.Y. Role of mitochondrial ROS in the brain: From physiology to neurodegeneration. FEBS Lett. 2018, 592, 692–702.

37. Daenen, K.; Andries, A.; Mekahli, D.; Van Schepdael, A.; Jouret, F.; Bammens, B. Oxidative stress in chronic kidney disease. Pediatr. Nephrol. 2018, 34, 975–991.

38. Galvan, D.L.; Green, N.H.; Danesh, F.R. The hallmarks of mitochondrial dysfunction in chronic kidney disease. Kidney Int. 2017, 92, 1051–1057.

39. Nistala, R.; Whaley-Connell, A.; Sowers, J.R. Redox Control of Renal Function and Hypertension. Antioxid. Redox Signal. 2008, 10, 2047–2089.

40. Rensvold, J.W.; Ong, S.-E.; Jeevananthan, A.; Carr, S.A.; Mootha, V.K.; Pagliarini, D.J. Complementary RNA and Protein Profiling Identifies Iron as a Key Regulator of Mitochondrial Biogenesis. Cell Rep. 2013, 3, 237–245.

41. Chen, W.-L.; Kang, C.-H.; Wang, S.-G.; Lee, H.-M. α-Lipoic acid regulates lipid metabolism through induction of sirtuin 1 (SIRT1) and activation of AMP-activated protein kinase. Diabetologia 2012, 55, 1824–1835.

42. Canto, C.; Auwerx, J. PGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr. Opin. Lipidol. 2009, 20, 98–105.

43. Chang, H.-C.; Guarente, L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol. Metab. 2013, 25, 138–145.

44. Chodari, L.; Aytemir, M.D.; Vahedi, P.; Alipour, M.; Vahed, S.Z.; Khatibi, S.M.H.; Ahmadian, E.; Ardalan, M.; Eftekhari, A. Targeting Mitochondrial Biogenesis with Polyphenol Compounds. Oxidative Med. Cell. Longev. 2021, 2021, 4946711.

45. Chambers, J.M.; Wingert, R.A. PGC-1α in Disease: Recent Renal Insights into a Versatile Metabolic Regulator. Cells 2020, 9, 2234.

46. Layal, K.; Perdhana, I.S.; Louisa, M.; Estuningtyas, A.; Soetikno, V. The effects of quercetin on oxidative stress and fibrosis markers in chronic kidney disease rat model. Med. J. Indones. 2017, 26, 169–177. [CrossRef]

47. Ruiz, S.; Pergola, P.E.; Zager, R.A.; Vaziri, N.D. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int. 2013, 83, 1029–1041.

48. Liesa, M.; Shirihai, O.S. Mitochondrial Dynamics in the Regulation of Nutrient Utilization and Energy Expenditure. Cell Metab. 2013, 17, 491–506.

49. Pernas, L.; Scorrano, L. Mito-Morphosis: Mitochondrial Fusion, Fission, and Cristae Remodeling as Key Mediators of Cellular Function. Annu. Rev. Physiol. 2016, 78, 505–531.

50. Putti, R.; Sica, R.; Migliaccio, V.; Lionetti, L. Diet impact on mitochondrial bioenergetics and dynamics. Front. Physiol. 2015, 6, 109.

51. Zhan, M.; Brooks, C.; Liu, F.; Sun, L.; Dong, Z. Mitochondrial dynamics: Regulatory mechanisms and emerging role in renal pathophysiology. Kidney Int. 2013, 83, 568–581.

52. Lahera, V.; Heras, N.D.L.; Farre, A.L.; Manucha, W.; Ferder, L. Role of Mitochondrial Dysfunction in Hypertension and Obesity. Curr. Hypertens. Rep. 2017, 19, 11.

53. Brooks, C.; Wei, Q.; Cho, S.-G.; Dong, Z. Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models. J. Clin. Investig. 2009, 119, 1275–1285.

54. Scheibye-Knudsen, M.; Fang, E.F.; Croteau, D.L.; Wilson, D.M.; Bohr, V.A. Protecting the mitochondrial powerhouse. Trends Cell Biol. 2014, 25, 158–170.

55. Ashrafi, G.; Schwarz, T.L. The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 2012, 20, 31–42.

56. Youle, R.J.; Narendra, D.P. Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 2011, 12, 9–14.

57. Wang, Y.; Cai, J.; Tang, C.; Dong, Z. Mitophagy in Acute Kidney Injury and Kidney Repair. Cells 2020, 9, 338.

58. Clark, A.J.; Parikh, S.M. Mitochondrial Metabolism in Acute Kidney Injury. Semin. Nephrol. 2020, 40, 101–113.

59. Tang, C.; Han, H.; Yan, M.; Zhuohua, Z.; Liu, J.; Liu, Z.; Chengyuan, T.; Tan, J.; Liu, Y.; Liu, H.; et al. PINK1-PRKN/PARK2 pathway of mitophagy is activated to protect against renal ischemia-reperfusion injury. Autophagy 2018, 14, 880–897.

60. Ferenbach, D.A.; Bonventre, J.V. Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat. Rev. Nephrol. 2015, 11, 264–276. [

61. Bravi, C.A.; Vertosick, E.; Benfante, N.; Tin, A.; Sjoberg, D.; Hakimi, A.A.; Touijer, K.; Montorsi, F.; Eastham, J.; Russo, P.; et al. Impact of Acute Kidney Injury and Its Duration on Long-term Renal Function After Partial Nephrectomy. Eur. Urol. 2019, 76, 398–403.

62. Forni, L.G.; Darmon, M.; Ostermann, M.; Straaten, H.M.O.-V.; Pettilä, V.; Prowle, J.; Schetz, M.; Joannidis, M. Renal recovery after acute kidney injury. Intensiv. Care Med. 2017, 43, 855–866.

63. Scammell, M.K.; Sennett, C.M.; Petropoulos, Z.; Kamal, J.; Kaufman, J.S. Environmental and Occupational Exposures in Kidney Disease. Semin. Nephrol. 2019, 39, 230–243.

64. Zheng, L.Y.; Sanders, A.P.; Saland, J.M.; Wright, R.O.; Arora, M. Environmental exposures and pediatric kidney function and disease: A systematic review. Environ. Res. 2017, 158, 625–648.

65. Granata, S.; Gassa, A.D.; Tomei, P.; Lupo, A.; Zaza, G. Mitochondria: A new therapeutic target in chronic kidney disease. Nutr. Metab. 2015, 12, 49.

66. Amani, H.; Habibey, R.; Shokri, F.; Hajmiresmail, S.J.; Akhavan, O.; Mashaghi, A.; Pazoki-Toroudi, H. Selenium nanoparticles for targeted stroke therapy through modulation of inflammatory and metabolic signaling. Sci. Rep. 2019, 9, 6044.

67. Liu, H.; Chen, Z.; Weng, X.; Chen, H.; Du, Y.; Diao, C.; Liu, X.; Wang, L. Enhancer of zeste homolog 2 modulates oxidative stressmediated pyroptosis in vitro and in a mouse kidney ischemia-reperfusion injury model. FASEB J. 2019, 34, 835–852.

68. Kamarauskaite, J.; Baniene, R.; Trumbeckas, D.; Strazdauskas, A.; Trumbeckaite, S. Caffeic Acid Phenethyl Ester Protects Kidney Mitochondria against Ischemia/Reperfusion Induced Injury in an In Vivo Rat Model. Antioxidants 2021, 10, 747.

69. Trumbeckaite, S.; Pauziene, N.; Trumbeckas, D.; Jievaltas, M.; Baniene, R. Caffeic Acid Phenethyl Ester Reduces Ischemia-Induced Kidney Mitochondrial Injury in Rats. Oxidative Med. Cell. Longev. 2017, 2017, 1697018.

70. Liu, Q.; Liang, X.; Liang, M.; Qin, R.; Qin, F.; Wang, X. Ellagic Acid Ameliorates Renal Ischemic-Reperfusion Injury Through NOX4/JAK/STAT Signaling Pathway. Inflammation 2019, 43, 298–309.

71. Roede, J.R.; Jones, D.P. Reactive species and mitochondrial dysfunction: Mechanistic significance of 4-hydroxynonenal. Environ. Mol. Mutagen. 2010, 51, 380–390.

72. Wang, H.; Guan, Y.; Karamercan, M.A.; Ye, L.; Bhatti, T.; Becker, L.B.; Baur, J.A.; Sims, C.A. Resveratrol Rescues Kidney Mitochondrial Function Following Hemorrhagic Shock. Shock 2015, 44, 173–180.

73. Chong, S.J.F.; Low, I.C.C.; Pervaiz, S. Mitochondrial ROS and involvement of Bcl-2 as a mitochondrial ROS regulator. Mitochondrion 2014, 19, 39–48.

74. Su, L.-J.; Zhang, J.-H.; Gomez, H.; Murugan, R.; Hong, X.; Xu, D.; Jiang, F.; Peng, Z.-Y. Reactive Oxygen Species-Induced Lipid Peroxidation in Apoptosis, Autophagy, and Ferroptosis. Oxidative Med. Cell. Longev. 2019, 2019, 5080843.

75. Jiang, G.; Liu, X.; Wang, M.; Chen, H.; Chen, Z.; Qiu, T. Oxymatrine ameliorates renal ischemia-reperfusion injury from oxidative stress through Nrf2/HO-1 pathway. Acta Cir. Bras. 2015, 30, 422–429.

76. Kumaran, K.S.; Prince, P.S.M. Caffeic acid protects rat heart mitochondria against isoproterenol-induced oxidative damage. Cell Stress Chaperones 2010, 15, 791–806.

77. Camello-Almaraz, C.; Gomez-Pinilla, P.J.; Pozo, M.J.; Camello, P.J. Mitochondrial reactive oxygen species and Ca2+ signaling. Am. J. Physiol. Cell Physiol. 2006, 291, C1082–C1088.

78. Robert, F.F.; Feissner, R.F.; Skalska, J.; Gaum, W.E.; Sheu, S.-S. Crosstalk signaling between mitochondrial Ca2+ and ROS. Front. Biosci. 2009, 14, 1197–1218.

79. Qu, J.; Chen, W.; Hu, R.; Feng, H. The Injury and Therapy of Reactive Oxygen Species in Intracerebral Hemorrhage Looking at Mitochondria. Oxidative Med. Cell. Longev. 2016, 2016, 2592935.

80. Basile, D.P.; Anderson, M.D.; Sutton, T.A. Pathophysiology of Acute Kidney Injury. Compr. Physiol. 2012, 2, 1303–1353.

81. Genchi, G.; Sinicropi, M.S.; Lauria, G.; Carocci, A.; Catalano, A. The Effects of Cadmium Toxicity. Int. J. Environ. Res. Public Health 2020, 17, 3782.

82. Zhang, Q.; Zhang, C.; Ge, J.; Lv, M.-W.; Talukder, M.; Guo, K.; Li, Y.-H.; Li, J.-L. Ameliorative effects of resveratrol against cadmium-induced nephrotoxicity via modulating nuclear xenobiotic receptor response and PINK1/Parkin-mediated Mitophagy. Food Funct. 2020, 11, 1856–1868.

83. Liu, L.; Tao, R.; Huang, J.; He, X.; Qu, L.; Jin, Y.; Zhang, S.; Fu, Z. Hepatic oxidative stress and inflammatory responses with cadmium exposure in male mice. Environ. Toxicol. Pharmacol. 2015, 39, 229–236.

84. Karaca, S.; Eraslan, G. The Effects of Flaxseed Oil on Cadmium-Induced Oxidative Stress in Rats. Biol. Trace Elem. Res. 2013, 155, 423–430.

85. Cannino, G.; Ferruggia, E.; Rinaldi, A.M. Proteins participating to the post-transcriptional regulation of the mitochondrial cytochrome c oxidase subunit IV via elements located in the 30 UTR. Mitochondrion 2009, 9, 471–480.

86. Xu, S.; Pi, H.; Zhang, L.; Zhang, N.; Li, Y.; Zhang, H.; Tang, J.; Li, H.; Feng, M.; Deng, P.; et al. Melatonin prevents abnormal mitochondrial dynamics resulting from the neurotoxicity of cadmium by blocking calcium-dependent translocation of Drp1 to the mitochondria. J. Pineal Res. 2016, 60, 291–302.

87. Khan, F.; Pham, D.T.N.; Kim, Y.-M. Alternative strategies for the application of aminoglycoside antibiotics against the biofilmforming human pathogenic bacteria. Appl. Microbiol. Biotechnol. 2020, 104, 1955–1976.

88. Walker, P.D.; Shah, S.V. Gentamicin enhanced production of hydrogen peroxide by renal cortical mitochondria. Am. J. Physiol. Physiol. 1987, 253, C495–C499.

89. Kinnally, K.W.; Peixoto, P.M.; Ryu, S.-Y.; Dejean, L.M. Is mPTP the gatekeeper for necrosis, apoptosis, or both? Biochim. Biophys. Acta 2011, 1813, 616–622.

90. Sepand, M.R.; Ghahremani, M.H.; Razavi-Azarkhiavi, K.; Aghsami, M.; Rajabi, J.; Keshavarz-Bahaghighat, H.; Soodi, M. Ellagic acid confers protection against gentamicin-induced oxidative damage, mitochondrial dysfunction, and apoptosis-related nephrotoxicity. J. Pharm. Pharmacol. 2016, 68, 1222–1232.

91. Zhang, S.; Zhong, X.; Yuan, H.; Guo, Y.; Song, D.; Qi, F.; Zhu, Z.; Wang, X.; Guo, Z. Interfering in apoptosis and DNA repair of cancer cells to conquer cisplatin resistance by platinum (iv) prodrugs. Chem. Sci. 2020, 11, 3829–3835.

92. Waseem, M.; Kaushik, P.; Parvez, S. Mitochondria-Mediated mitigatory role of curcumin in cisplatin-induced nephrotoxicity. Cell Biochem. Funct. 2013, 31, 678–684.

93. Kumar, M.; Dahiya, V.; Kasala, E.R.; Bodduluru, L.N.; Lahkar, M. The renoprotective activity of hesperetin in cisplatin-induced nephrotoxicity in rats: Molecular and biochemical evidence. Biomed. Pharmacother. 2017, 89, 1207–1215.

94. Szewczyk, A. Mitochondria as a Pharmacological Target. Pharmacol. Rev. 2002, 54, 101–127.

95. Sung, M.J.; Kim, D.H.; Jung, Y.J.; Kang, K.P.; Lee, A.S.; Lee, S.; Kim, W.; Davaatseren, M.; Hwang, J.-T.; Kim, H.-J.; et al. Genistein protects the kidney from cisplatin-induced injury. Kidney Int. 2008, 74, 1538–1547.

96. Guerrero-Beltrán, C.E.; Mukhopadhyay, P.; Horváth, B.; Rajesh, M.; Tapia, E.; García-Torres, I.; Pedraza-Chaverri, J.; Pacher, P. Sulforaphane, a natural constituent of broccoli, prevents cell death and inflammation in nephropathy. J. Nutr. Biochem. 2012, 23, 494–500.

97. Wang, Z.; Sun, W.; Sun, X.; Wang, Y.; Zhou, M. Kaempferol ameliorates Cisplatin induced nephrotoxicity by modulating oxidative stress, inflammation and apoptosis via ERK and NF-κB pathways. AMB Express 2020, 10, 1–11.

98. Ciarcia, R.; Damiano, S.; Florio, A.; Spagnuolo, M.; Zacchia, E.; Squillacioti, C.; Mirabella, N.; Florio, S.; Pagnini, U.; Garofano, T.; et al. The Protective Effect of Apocynin on Cyclosporine A-Induced Hypertension and Nephrotoxicity in Rats. J. Cell. Biochem. 2015, 116, 1848–1856.

99. Tedesco, D.; Haragsim, L. Cyclosporine: A Review. J. Transplant. 2012, 2012, 230386.

100. Niemann, C.U.; Saeed, M.; Akbari, H.; Jacobsen, W.; Benet, L.Z.; Christians, U.; Serkova, N.; Saeed, M. Close Association Between the Reduction in Myocardial Energy Metabolism and Infarct Size: Dose-Response Assessment of Cyclosporine. J. Pharmacol. Exp. Ther. 2002, 302, 1123–1128.

101. Serkova, N.; Jacobsen, W.; Niemann, C.U.; Litt, L.; Benet, L.Z.; Leibfritz, D.; Christians, U. Sirolimus, but not the structurally related RAD (everolimus), enhances the negative effects of cyclosporine on mitochondrial metabolism in the rat brain. J. Cereb. Blood Flow Metab. 2001, 133, 875–885.

102. Serkova, N.; Klawitter, J.; Niemann, C.U. Organ-Specific response to inhibition of mitochondrial metabolism by cyclosporine in the rat. Transpl. Int. 2003, 16, 748–755.

103. Rehman, H.; Krishnasamy, Y.; Haque, K.; Thurman, R.G.; Lemasters, J.J.; Schnellmann, R.G.; Zhong, Z. Green Tea Polyphenols Stimulate Mitochondrial Biogenesis and Improve Renal Function after Chronic Cyclosporin A Treatment in Rats. PLoS ONE 2013, 8, e65029.

104. Moon, D.; Kim, J. Cyclosporin A aggravates hydrogen peroxide-induced cell death in kidney proximal tubule epithelial cells. Anat. Cell Biol. 2019, 52, 312–323.

105. Wu, Q.; Li, W.; Zhao, J.; Sun, W.; Yang, Q.; Chen, C.; Xia, P.; Zhu, J.; Zhou, Y.; Huang, G.; et al. Apigenin ameliorates doxorubicininduced renal injury via inhibition of oxidative stress and inflammation. Biomed. Pharmacother. 2021, 137, 111308.

106. Alagal, R.I.; AlFaris, N.A.; Alshammari, G.M.; Altamimi, J.Z.; AlMousa, L.A.; Yahya, M.A. Kaempferol attenuates doxorubicinmediated nephropathy in rats by activating SIRT1 signaling. J. Funct. Foods 2021, 89, 104918.

107. Kocahan, S.; Dogan, Z.; Erdemli, E.; Taskin, E. Protective Effect of Quercetin against Oxidative Stress-Induced Toxicity Associated with Doxorubicin and Cyclophosphamide in Rat Kidney and Liver Tissue. Iran. J. Kidney Dis. 2017, 11, 124–131.

108. Chénais, B.; Andriollo, M.; Guiraud, P.; Belhoussine, R.; Jeannesson, P. Oxidative stress involvement in chemically induced differentiation of K562 cells. Free. Radic. Biol. Med. 2000, 28, 18–27.

109. Sutariya, B.; Saraf, M. α-asarone reduce proteinuria by restoring antioxidant enzymes activities and regulating necrosis factor κB signaling pathway in doxorubicin-induced nephrotic syndrome. Biomed. Pharmacother. 2017, 98, 318–324.

110. Hekmat, A.S.; Chenari, A.; Alipanah, H.; Javanmardi, K. Protective effect of alamandine on doxorubicin-induced nephrotoxicity in rats. BMC Pharmacol. Toxicol. 2021, 22, 31.

111. Pedrycz, A.; Czerny, K. Immunohistochemical study of proteins linked to apoptosis in rat fetal kidney cells following prepregnancy adriamycin administration in the mother. Acta Histochem. 2008, 110, 519–523.

112. Pedrycz, A.; Wieczorski, M.; Czerny, K. Late effects of adriamycin single dose on fetal rat kidney—Ultrastructural assessment. Environ. Toxicol. Pharmacol. 2005, 20, 157–160.

113. de Zeeuw, D.; Remuzzi, G.; Parving, H.-H.; Keane, W.F.; Zhang, Z.; Shahinfar, S.; Snapinn, S.; Cooper, M.E.; Mitch, W.E.; Brenner, B.M. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: Lessons from RENAAL. Kidney Int. 2004, 65, 2309–2320.

114. Cepas, V.; Collino, M.; Mayo, J.C.; Sainz, R.M. Redox Signaling and Advanced Glycation Endproducts (AGEs) in Diet-Related Diseases. Antioxidants 2020, 9, 142.

115. Tiwari, B.K.; Pandey, K.B.; Abidi, A.B.; Rizvi, S.I. Markers of Oxidative Stress during Diabetes Mellitus. J. Biomark. 2013, 2013, 378790.

116. Forbes, J.M.; Coughlan, M.T.; Cooper, M.E. Oxidative Stress as a Major Culprit in Kidney Disease in Diabetes. Diabetes 2008, 57, 1446–1454.

117. A Nath, K.; Norby, S.M. Reactive oxygen species and acute renal failure. Am. J. Med. 2000, 109, 665–678.

118. Fernandes, S.M.; Cordeiro, P.M.; Watanabe, M.; da Fonseca, C.D.; Vattimo, M.D.F.F. The role of oxidative stress in streptozotocininduced diabetic nephropathy in rats. Arch. Endocrinol. Metab. 2016, 60, 443–449.

119. Malik, S.; Suchal, K.; Khan, S.I.; Bhatia, J.; Kishore, K.; Dinda, A.K.; Arya, D.S. Apigenin ameliorates streptozotocin-induced diabetic nephropathy in rats via MAPK-NF-κB-TNF-α and TGF-β1-MAPK-fibronectin pathways. Am. J. Physiol. Physiol. 2017, 313, F414–F422.

120. Altamimi, J.Z.; AlFaris, N.A.; Alshammari, G.M.; Alagal, R.I.; Aljabryn, D.H.; Aldera, H.; Alrfaei, B.M.; Alkhateeb, M.A.; Yahya, M.A. Ellagic acid protects against diabetic nephropathy in rats by regulating the transcription and activity of Nrf2. J. Funct. Foods 2021, 79, 104397.

121. Abdou, H.M.; Elkader, H.-T.A.E.A. The potential therapeutic effects of Trifolium alexandrinum extract, hesperetin, and quercetin against diabetic nephropathy via attenuation of oxidative stress, inflammation, GSK-3β and apoptosis in male rats. Chem. Interact. 2021, 352, 109781.

122. Rius-Pérez, S.; Torres-Cuevas, I.; Millán, I.; Ortega, Á.L.; Pérez, S. PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism. Oxid. Med. Cell. Longev. 2020, 2020, 1452696.

123. Bao, L.; Cai, X.; Dai, X.; Ding, Y.; Jiang, Y.; Li, Y.; Zhang, Z.; Li, Y. Grape seed proanthocyanidin extracts ameliorate podocyte injury by activating peroxisome proliferator-activated receptor-γ coactivator 1α in low-dose streptozotocin-and high-carbohydrate/highfat diet-induced diabetic rats. Food Funct. 2014, 5, 1872–1880.

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.)