Small Molecule Natural Products Targeting Nrf2-HO-1 Signaling: History
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Contributor:
Md Jamal Uddin
,
Hunjoo Ha
,
Eehyun Kim
,
Md Abdul Hannan

The global burden of chronic kidney disease (CKD) intertwined with cardiovascular disease has become a major health problem. Oxidative stress (OS) plays an important role in the pathophysiology of CKD. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant responsive element (ARE) antioxidant system plays a critical role in kidney protection by regulating antioxidants during OS. Heme oxygenase-1 (HO-1), one of the targets of Nrf2-ARE, plays an important role in regulating OS and is protective in a variety of human and animal models of kidney disease. Thus, activation of Nrf2-HO-1 signaling may offer a potential approach to the design of novel therapeutic agents for kidney diseases.

  • chronic kidney diseases
  • oxidative stress
  • Nrf2
  • HO-1
  • small molecule natural products

1. Introduction

The incidence and prevalence of chronic kidney disease (CKD) patients is increasing worldwide. The prevalence of CKD between male and female patients is not constant between countries, however, kidney functions decline faster in males than females [1]. Importantly, CKD is not only a risk factor for increasing global mortality but it is also a critical factor involved in cardiovascular disease (CVD) [2]. The close link between CKD and CVD has been known for a long time [3][4][5]. Not only traditional risk factors such as hypertension, dyslipidemia, and diabetes, but also non-traditional risk factors such as disturbed minerals and vitamins in CKD may play important roles in the progression of CVD. The current treatment options for CKD are controlling blood pressure, serum glucose, and serum lipid profile [6], as well as a modification of lifestyle [7][8]. Since the efficacy of the current therapeutic strategy is still limited [9], there is a need to develop a more effective therapeutic option for treating CKD. Although the exact mechanism involved in the development of CKD is elusive, many lines of evidence strongly suggest that oxidative stress (OS) plays a critical role in the progression of CKD [10][11][12][13].
OS is an imbalance between cellular reactive oxygen species (ROS) levels and antioxidant enzymes, leading to a pathological condition. ROS regulates various signaling pathways, including the growth and differentiation of cells, mitogenesis, production, and breakdown of the extracellular matrix (ECM), inflammation, and apoptosis [14]. OS-mediated damaging effects of cells are controlled by activating the antioxidant defense system. OS has also been noticed to be affected by sex hormones in ischemic kidney injury [15]. Unfortunately, there is an impairment of antioxidative defense and a reduced activity of antioxidant enzymes in CKD [16]. Hence, promoting the endogenous antioxidants defense system may become an important strategy in inhibiting OS-mediated cellular damage in CKD.
Phytochemicals and other natural products are cytoprotective against OS by scavenging oxygen-free radicals and enhancing the level of antioxidants [17]. The literature on protective effects of antioxidant natural products against CKD has been reported [18][19][20]. Nuclear factor erythroid 2-related factor 2 (Nrf2) is the master regulator of the cellular antioxidant defense system [17]. Studies review that augmentation of Nrf2 activity prevents the progression of acute kidney injury (AKI) to CKD transition [21][22]. Natural bioactive compounds and their sources have been demonstrated to have kidney protective potential by activating Nrf2 in experimental CKD models [23][24]. In a recent review on clinical studies, bardoxolone methyl (CDDO-me), a semi-synthetic triterpenoid activating the Nrf2 pathway, has been reported as an effective therapeutic for diabetic kidney disease (DKD), although it has limitations in that it increases the risk of heart failure [25]. Heme oxygenase-1 (HO-1), one of the target molecules of Nrf2, attenuates the overall production of ROS through its ability to degrade heme and to produce carbon monoxide (CO), biliverdin/bilirubin, and the release of free iron. Induction of HO-1 mediates many beneficial effects in the cardiovascular system and kidney [26]. Also, the modulatory role of HO-1 has been reported in various kidney injury models including CKD [27][28][29][30][31][32][33][34]. Several natural HO-1 inducers and their therapeutic applications in various diseases, including CKD, have been reported [35].

2. Small Molecule Natural Products Activating Nrf2-HO-1 Signaling

A substantial quantity of natural products has been reported to confer renoprotection and improve disease outcomes of the various types of CKD, primarily through activating the Nrf2/HO-1 antioxidant defense systems and attenuating the proinflammatory signaling pathways. Here, researchers reviewed the existing literature over the past decade to compile comprehensive information on the kidney protective potential of naturally occurring compounds. Experimental and disease models, the pathobiology involved, the research outcomes, and the molecular markers altered by these compounds are summarized in Table 1 and Table 2 and Figure 1. To facilitate the discussion, researchers have categorized the kidney protective effects of these natural compounds into two distinct chemical groups: phenolic and non-phenolics. This categorization also highlights common bioactive compounds, belonging to phenolic group which represents the largest chemical class showing enormous bioactivity with the potential to be future drug candidates.
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Figure 1. Protective effects of small-molecule natural products on OS in CKD. Osthole and SAA enhance the activation of the Akt/Nrf2/HO-1 signaling pathway with suppression of NF-kB and TGFβ1, consequently attenuating OS, inflammation, and fibrosis. OB induces the phosphorylation of GSK3β, which inhibits Fyn-mediated Nrf2 nuclear export, and activates the transcription of Nrf2-driven antioxidant genes. Expression of SIRT1, which inhibits NF-kB activity, and the activation of Nrf2 are enhanced by aucubin, melatonin, and RSV, which also upregulates SIRT3, resulting in amelioration of kidney injury. Dioscin upregulates SIRT3 level, promotes Nrf2, and suppresses Keap1 expression, resulting in inhibition of inflammation, lipid metabolism, OS, and kidney fibrosis. PD increases the CKIP-1 expression level and promotes the interaction of CKIP-1 with Nrf2, consequently activating the Nrf2-ARE antioxidative pathway. Allicin, AST, curcumin, EASM, EGCG, ILQ, and PQQ attenuate OS via the Nrf2/HO-1 signaling pathway with inhibition of Keap1, and they also reduce TGFβ-mediated fibrosis and NF-kB-induced inflammation. In the cases of an anti-fibrotic effect of apigenin, ASD, baicalein, BA, CGA, CTS, ERG, OL, and SFN, AMP, antroq, artemisinin, berbeine, calycosin, SA, SIN, and TRIG, they are mediated not only by upregulation of the Nrf2/HO-1 antioxidant signaling pathway and downregulation of NF-kB-induced inflammation, but also via TGFβ suppression. Treatments with citral, NGR1, OA, SAL, and silibinin have potency for anti-apoptotic effects with regulation of Bcl2/Bax and caspase3. The decrease in the NLRP3 inflammasome was also observed in treatments with baicalein, EGCG, and OL. L-mimosine activates HIF1α, which upregulates renoprotective HIF target genes, such as VEGF, HO-1, and GLUT1, and decreases fibrosis markers. AMP, ampelopsin; Antroq, antroquinonol; ASD, akebia saponin D; AST, astaxanthin; BA, betulinic acid; CGA, chlorogenic acid; CTS, cryptotanshinone; EASM, ethyl acetate extract of Salvia miltiorrhiza; EGCG, Epigallocatechin gallate; ERG, ergone; GSK3β, glycogen synthase kinase 3β; HIFα, hypoxia-inducible factor α; ILQ, isoliquiritin; NGR1, notoginsenoside R1; OA, oleanolic acid; OB, obacunone; OL, oleuropein; PD, polydatin; PQQ, pyrroloquinoline quinone; RSV, resveratrol; SA, sinapic acid; SAA, salvianolic acid A; SAL, salidroside; SFN, sulforaphane; SIN, sinomenine; TRIG, trigonelline.
Table 1. Kidney protective effects provided by phenolic compounds of phytochemicals targeting the Nrf2-HO-1 signaling pathway.
No. Modulator Chemical Class and Natural Sources Experimental Model Disease Model Pathobiology Involved Major Research Outcomes Molecular Markers Ref.
Phenolic compounds
1 Ampelopsin Flavonoid; Ampelopsis grossedentata HG-stimulated hGMCs OS OS, ECM accumulation Amelioration of OS and ECM accumulation ↓ROS, ↓MDA, ↑SOD, ↓Nox2,
↓Nox4, ↓NADPH, ↓FN, ↓Col IV, ↑n-Nrf2, ↑HO-1,		 [36]
2 Apigenin Flavonoid; common fruits and vegetables HG-treated HK-2 cells Oxidative damage Oxidative damage Decrease in apoptosis, inhibition of OS, and inflammatory response ↓LDH, ↓MDA, ↑SOD, ↑CAT, ↓TNFα, ↓IL-1β, ↓IL-6, ↑Nrf2, ↑HO-1 [37]
3 Astaxanthin Xanthophyll carotenoid; algae, shrimp, lobster, crab, salmon, and other organisms STZ-injected rat DKD ECM accumulation Amelioration of kidney injury ↓FN, ↓TGFβ1, ↓ICAM-1 [38]
HG-treated GMCs Kidney fibrosis OS Increase in antioxidative capacity ↓FN, ↓TGFβ1, ↓ICAM-1, ↑SOD,
↓MDA, ↓ROS, ↓DHE, ↑n-Nrf2,
↓keap1, ↓SOD-1, ↓Nqo1, ↓HO-1
Adriamycin-treated BALB/c mice FSGS OS, inflammation Anti-inflammation, antioxidation ↓TGFβ1, ↓collagen1, ↓α-SMA, ↓MDA, ↑GSH, ↑SOD, ↑CAT, (serum: ↓IL-1 β, IL-18), ↑Nrf2, ↓NLRP3 [39]
4 Baicalein Flavonoid; roots of Scutellaria baicalensis Georgi Pristine -injected BALB/c mice LN OS, inflammation Attenuation of kidney dysfunction, antioxidation, anti-inflammation, inhibition of MDSC expansion ↓IL-1b, ↓IL-18, ↓O2¯˙,
↑ GPx, ↑Nrf2, ↑HO-1, ↓ NLRP3,
↓Casp-1, ↓mIL-1 β, ↓p-NF-kB		 [40]
LPS-primed spleen-derived MDSCs OS, inflammation ↓ROS, ↓IL-1β, ↓IL-18, ↑Nrf2, ↑HO-1, ↓NLRP3, ↓mIL-1β/pro-IL-1β,
↓Casp-1-p20/pro-casp-1-p45, ↓p-NF-kB/NF-kB, ↓Ang-1, ↓p47phox,
↓GP91phox, ↓iNOS
5 Calycosin Isoflavone; root of Astragalus membranaceus HFD-fed/ STZ-injected SD rat DKD Inflammation, OS, fibrosis Inhibition of inflammatory, oxidative, and fibrotic events ↓IL-33, ↓ST2, ↓NF-kB p65, ↓TNFα, ↓IL-1 β, ↓IL-6, ↑Nrf2, ↓MDA, ↓TGFβ [41]
6 Chlorogenic acid Cinnamate ester; coffee, fruits, and vegetables STZ-injected and HFD-fed SD rat DKD OS, inflammation Relieve kidney injury, mitigation of OS, inflammation ↓MDA, ↑SOD, ↑GSH-Px, ↑n-Nrf2,
↑HO-1, ↓IL-6, ↓TNFα, ↓IL-1 β, ↑c-NF-kB, ↓n-NF-kB, ↑IkBα, ↓p-IkBα,		 [42]
HG-treated rat mesangial cell line (HBZY-1) Mitigation of OS, inflammation, increase in cell proliferation ↑n-Nrf2, ↑HO-1, ↑c-NF-kB, ↓n-NF-kB, ↑IkBα, ↓p-IkBα, ↓IL-6, ↓TNFα, ↓IL-1 β
7 Cryptotanshinone Quinoid diterpene; Salvia miotiorrhiza bunge UUO-operated mice Kidney fibrosis OS, inflammation Attenuation of OS and inflammation ↓collagen-1, ↓FN, ↓CD68,
↓CD3, ↑IkBα, ↓NF-kB p65, ↑SOD2, ↑CAT, ↑GSH, ↓MDA, ↑Nuclear Nrf2, ↓cytosolic Nrf2, ↑HO-1		 [43]
8 Curcumin Curcuminoid; turmeric (Curcuma longa) 5/6 nephrectomy Wistar rat CKD OS, inflammation Protection of kidney function, antioxidant, anti-inflammation ↓Nox4, ↑eNOS, ↓nitrotyrosine,
↓MCP-1, ↓Keap-1, ↑Nrf2, ↑GPx-1, ↑CAT, ↑SOD-1, ↓phospho serine D1R		 [44]
0.25% Adenine -diet rat CKD OS, inflammation Amelioration of kidney function and OS ↓IL-1 β, ↓IL-6, ↓TNFα, ↑cycstatin C, ↓adiponecitn, ↑sclerostin, ↑SOD,
↑Nrf2, ↑GSH reductase. ↓ caspase3		 [45]
HG-treated NRK-52E cells OS OS Increase in cell viability, inhibition of EMT ↑E-cadherin, ↓α-SMA, ↑Nrf2, ↑HO-1 [46]
9 Epigallocatechin-3 -Gallate Polyphenol; Dried leaves of tea plant (Camellia sinensis) STZ-injected mice DKD Oxidative damage, inflammation, Anti-OS ↓TGFβ1, ↓PAI-1, ↓ICAM-1, ↓VCAM-1, ↓MDA, ↓iNOS, ↓3-NT, ↑Nqo1, ↑HO-1, ↑t-Nrf2, ↑c-Nrf2, ↑n-Nrf2, ↑n-Nrf2/t-Nrf2 [47]
HG-cultured MMC ↑t-Nrf2, ↑c-Nrf2, ↑n-Nrf2, ↑Nqo1, ↑HO-1, ↓MDA, ↓iNOS, ↓VCAM-1,
↓ICAM-1, ↓COL4, ↓FN
NZB/W F1 lupus-prone mice LN OS Antioxidant and anti-inflammation ↑Nrf2, ↓p47phox, ↑Nqo1, ↑HO-1, ↑GPx, ↓CD3, ↓F4/80, ↓NF-kB,
↓NLRP3, ↓IL-1 β, ↓IL-18, ↓casp1-p20,		 [48]
UUO mice CKD OS, inflammation Kidney function improvement, prevention of OS and inflammation ↑SOD, ↑CAT, ↑GSH-Px, ↓MPO,
↓TNFα, ↓IL-6, ↓IL-1 β, ↑IkBα, ↓p-IkBα, ↓NF-kB, ↑n-Nrf2, ↑HO-1, ↑t-bilirubin		 [49]
10 Ethyl acetate extract of Saliva miltiorrhiza Diterpenoids, phenolic compounds, flavonoids, triterpenoids; dried root of Salvia miltiorrhiza Bunge STZ-injected mice DKD Oxidative stress Antioxidation, attenuation of kidney dysfunction ↑Nrf2, ↑HO-1, ↑Nqo1, ↓Keap1 [50]
HG-treated SV40-MES-13 MMCs hyperglycemia Antioxidation ↓ROS, ↑Nrf2, ↑HO-1, ↑Nqo1,
↓Keap1
11 Isoliquiritin Flavonoid glycoside; Chinese licorice (Glycyrrhiza uralensis) Cationic BSA-injected SD rat MGN Inflammation and OS Antioxidative, anti-inflammatory activities ↓Keap1, ↑Nrf2, ↓n-Nrf2, ↑c-Nrf2, ↑HO-1, ↑Nqo1, ↓MDA, ↓NO, ↑SOD, ↑CAT, ↑GPx, ↑GSH, ↓NF-kB p65, ↓nuclear NF-kB p65, ↑cyclic NF-kB, ↓IKKb, ↓p-IKKb, ↓TNFα, ↓IL-1 β, ↓COX2, ↓iNOS, ↓p38 MAPK, ↓p-p38 MAPK [51]
12 Oleuropein, peracetylatedoleuropein Secoiridoid; olive leaves, roots, and unprocessed olive drupes Pristine -injected BALB/c mice LN Inflammation and OS Amelioration of kidney abnormalities, inhibition of proinflammation, antioxidation ↓MMP-3, ↓iNOS, ↓mPGEs-1, ↓PGE2, ↑Nrf2, ↑HO-1, ↓pSTAT3, ↓NF-kB-p65, ↑IkBα, ↓pp38, ↓pJNK, ↓pERK1/2
↓NLRP3, ↓ASC, ↓IL-18, ↓ IL-1β,
↓cleaved caspase-1, ↓cleaved caspase 11		 [52]
13 Osthole Coumarin; Fructus Cnidii 2% adenine suspension -received rat CKD Inflammation Protection of kidney function, antiinflammation ↓TNFα, ↓IL-6, ↓IL-8, ↓NF-kB/p65,
↓TGFβ1, ↓MCP-1, ↑p-Akt/Akt, ↑Nrf2		 [53]
14 Polydatin Stilbenoid glucoside; Polygonum cuspidatum Sieb.et Zucc STZ-injected diabetic mice DKD OS Improvement of antioxidative effect and kidney dysfunction ↑CKIP-1, ↑Nrf2, ↑HO-1, ↑SOD1,
↓FN, ↓ICAM-1, ↓MDA, ↑t-SOD		  
HG-treated rat GMCs ↑Nrf2, ↓Keap1, ↑n-Nrf2, ↓n-CKIP-1, ↑ARE binding activity, ↑HO-1, ↑SOD1, ↓DHE, ↓H2O2, ↓FN, ↓ICAM-1
15 Resveratrol Phytoalexin; red grapes (Vitis vinifera L.), peanuts (Arachis spp.), berries (Vaccinium spp.) STZ-induced Wistar rat DKD OS Anti-inflammation, Anti-OS ↓iNOS, ↓NF-kB, ↓Nrf2, ↓NGAL, ↓IL-1β, ↓IL-6, ↓IL-8, ↓TNFα [54]
4-hydroxy-2-hexenal-treated mouse cortical collecting duct cells (M1) OS ↓nuclear p65, ↑cytosol IkB, ↑SIRT1,
↓Nox4, ↓COX2, ↑AQP2, ↓pERK/ERK, ↓pJNK/JNK, ↓pP38/P38, ↓Nrf2,
↑Keap1		 [55]
16 Rotenone Isoflavonone; seeds and stems of jicama vine plant, the roots of Fabaceae, etc. UUO-operated mice Kidney fibrosis Mitochondrial abnormality Anti-OS, anti-inflammation, anti-fibrosis ↓TBARS, ↓HO-1, ↓TNFα, ↓IL-1β,
↓ICAM1, ↓collagen I, ↓FN, ↓α-SMA, ↓PAI-1, ↓collagen III, ↓TGFβ,
↑mtDNA, ↑mtNd1		 [56]
17 Salidroside phenylpropanoid glycoside; plant Rhodiola rosea HG-treated mouse podocytes Apoptosis Apoptosis Improvement of cell viability ↓Caspase-9, ↓caspase-3, ↑HO-1, ↑p-ILK/ILK, ↑p-Akt/Akt, ↑p-ERK/ERK, ↑p-JNK/JNK, ↓p-p38/p38, ↑Nrf2 [57]
18 Salvianolic acid A Polyphenol derivative; root of Salvia miltiorrhiza STZ-injected mice DKD OS Anti-OS ↓VCAM-1, ↑HO-1, ↓α-SMA,
↓NT, ↓DHE, ↑GPx-1		 [58]
HG-treated HK-2 cells ↑HO-1, ↓α-SMA, ↓p65, ↓ROS
5/6 nephrectomized SD rats CKD OS OS attenuation, ↑t-SOD, ↑GPx, ↑CAT, ↓MDA, ↓ROS, ↓Nox4, ↑p-Akt/Akt, ↑p-GSK3β/GSK3β, ↑p-Nrf2/Nrf2, ↑HO-1 [59]
H2O2-treated/LPS-treated HK-2 cells Cell viability improvement, decrease in OS ↑t-SOD, ↑GPx, ↑CAT, ↓MDA, ↓ROS, ↓Nox4, ↑p-Akt/Akt, ↑p-GSK3β/GSK3β, ↑n-Nrf2, ↑HO-1, ↓p-NF-kB p65/NF-kB p65, ↓ICAM-1, ↓p-NF-kB p65, ↓ICAM-1, ↑n-Nrf2, ↑HO-1
19 Silibinin Flavonoliganas: milk thistle seeds Arsenic -induced rat CKD Inflammation Attenuation of OS, inflammation, and apoptosis ↓TNFα, ↓iNOS, ↓NO, ↓NF-kB,
↓Caspase-3, ↓NADPH oxidase, ↑Nrf2		 [60]
20 Sinapnic acid Hydroxycinnamic acid; wine, vinegar STZ-injected rat DKD OS, inflammation Amelioration of OS and inflammation ↑CAT, ↑GPx, ↑SOD, ↓TNFα, ↓IL-6, ↓NO2, ↓MDA, ↓TFGβ, ↑HO-1,
↑Nrf2, ↓NF-kB, ↑IkBα, ↑Bcl2,
↓Caspase3, ↓Bax		 [61]
AQP2, aquaporin 2; α-SMA, α-smooth muscle actin; BSA, bovine serum albumin; CAT, catalase; CKD, chronic kidney disease; COX2, cyclooxygenase; DHE, dihydroethidium; DKD, diabetic kidney disease; ECM, extracellular matrix; EMT, epithelial-to-mesenchymal transition; eNOS, endothelial nitric oxide synthase; FN, fibronectin; GMCs, glomerular mesangial cells; GPx, glutathione peroxidase; GSK3β, glycogen synthase kinase 3β; HFD, high fat diet; HG, high glucose; HO-1, Heme oxygenase-1; ICAM, intercellular adhesion molecule 1; iNOS, inducible nitric oxide synthase; LDH, lactate dehydrogenase; LN, lupus nephritis; LPS, lipopolysaccharide; MCP-1, monocyte chemoattractant protein-1; MDA, malondialdehyde; MDSCs, myeloid-derived suppressor cells; MGN, membranous glomerulonephritis; MMCs, mouse mesangial cells; NGAL, neutrophil gelatinase-associated lipocalin; NLRP3, NLR family pyrin domain containing 3; Nqo1, NADPH quinone oxidoreductase; Nrf2, nuclear factor erythroid 2-related factor 2; MPO, myeloperoxidase; NT, nitrotyrosine; OS, oxidative stress; PAI-1, plasminogen activator inhibitor-1; SOD, superoxide dismutase; STZ, streptozotocin; TBARS, thiobarbituric acid reactive substances; UUO, unilateral ureteral obstruction; VCAM, vascular cell adhesion molecule 1.
Table 2. Kidney protective effects provided by non-phenolic compounds of phytochemicals targeting the Nrf2-HO-1 signaling pathway.
No. Modulator Chemical Class and Natural Sources Experimental Model Disease Model Pathobiology Involved Major Research Outcomes Molecular Markers Ref.
Non-phenolic compounds
1 Akebia Saponin D triterpenoid saponin; Dipsaci Radix STZ-injected mice DKD OS, inflammation Amelioration of kidney damage, inflammation, OS, and apoptosis ↓TNFα, ↓IL-1β, ↓IL-6, ↓MCP-1,
↓ROS, ↓MDA, ↓LDH, ↑SOD, ↑Bcl2, ↓Bax, ↓cleaved caspase3/caspase3,
↓cleaved caspase9/caspase9, ↑n-Nrf2, ↓p-NF-kB/t-NF-kB, ↑HO-1, ↑Nqo1, ↓p-IkBα/t-IkBα		 [62]
HG-treated HK-2 cells ↓TNFα, ↓IL-1β, ↓IL-6, ↓MCP-1,
↓ROS, ↓MDA, ↓LDH, ↑SOD, ↑Bcl2, ↓Bax, ↓cleaved caspase3/caspase3,
↓cleaved caspase9/caspase9, ↑Nrf2,
↓p-NF-kB/t-NF-kB, ↑HO-1, ↑Nqo1, ↓p-IkBα/t-IkBα
2 Allicin Diallyl thiosulfinate; garlic (Allium sativum L.) 5/6 nephrectomy Wistar rat CKD Fibrosis, OS Antihypertensive and antioxidant effects ↑AT1R, ↑AT2R, ↑Nrf2, ↓Keap1,
↑CAT, ↑SOD, ↓HO-1, ↑eNOS		 [63]
3 Antroquinonol Enone; mushroom (Antrodia camphorate) Adriamycin -injected BALB/c mice FSGS OS Decrease in kidney dysfunction, anti-OS, anti-inflammation ↓desmin, ↓O2●−, (serum, urine ↓ O2●−, ↓NO), ↓DHE, ↓p47phox, ↑Nrf2, ↑GPx, ↓NF-kB p65, ↓MCP-1, ↓IL-6, ↓CD3, ↓F4/80, ↓Col I, ↓Col III, ↓Col IV, ↓TGFβ1 [64]
4 Artemisinin sesquiterpene lactones; Asteraceae Artemisia annua STZ-injected rat DKD OS Amelioration of kidney dysfunction and OS ↓MDA, ↑t-SOD, ↑GPx, ↓TGFβ1, ↑t-Nrf2, ↑n-Nrf2, ↑HO-1, ↑Nqo1 [65]
5 Aucubin iridoid glycoside; leaf of Eucommia ulmoides HFD-fed and STZ-injected mice DKD OS, inflammation Amelioration of kidney dysfunction, anti-inflammation, anti-OS ↓FN, ↓collagen IV, ↓MDA,
↑SOD, ↑CAT, ↑GSH/T-GSH, ↓TNFα, ↓IL-6, ↓IL-1β, ↓p65, ↓IkBα, ↑Nrf2, ↑HO-1, ↑Nqo1, ↑FOXO3α, ↓p-FOXO3α/FOXO3α, ↑SIRT1, ↑SIRT3,
↓Ac-FOXO3α/FOXO3α		 [66]
6 Berberine isoquinoline alkaloid; Coptidis Rhizoma and Cortex Phellodendri STZ-injected mice DKD OS Anti-fibrosis ↓α-SMA, ↓collagen-1, ↑Nrf2,
↑NQO1, ↑HO-1		 [67]
HG-treated NRK 52E cells EMT ↓E-cadherin, ↓α-SMA, ↑n-Nrf2,
↑Nqo1, ↑HO-1, ↓p-Smad2, ↓p-Smad3
7 Betulinic acid pentacyclic triterpenoid; from the outer bark of white birch trees (Betula alba) STZ-injected SD rat DKD OS Anti-OS ↓IL-1 β, ↓IL-6, ↓MDA, ↑SOD, ↑CAT, ↑p-AMPK/AMPK, ↓p-IkBα/IkBα, ↓p-NF-kB/NF-kB, ↑Nrf2, ↑HO-1 [68]
8 Citral Terpeonids; Litsea cubeba Adriamycin -injected BALB/c mice FSGS OS Amelioration of kidney dysfunction, anti-OS, anti-inflammation, anti-apoptosis ↓O2¯˙, (serum, urine ↓O2¯˙, ↓NO), ↓DHE, ↓p47phox, ↑Nrf2, ↑Nqo1, ↑HO-1, ↓desmin, ↓TUNEL, ↓Casp-3p17, ↓Casp-9p37, ↓Bax/Bcl2, ↓pNF-kB p65, ↓MCP-1, ↓ CD3, ↓F4/80 [69]
LPS-treated RAW 264.7 macrophages OS ↓NO, ↓NF-kB, ↓IL-6, ↓TNFα, ↓IL-1β, ↓p-ERK1/2(10min), ↓p-JNK1/2(15,30min)
9 Dioscin Steroid saponin; Dioscoreae rhizoma 10% fructose -fed mice CKD Oxidative damage, lipid metabolism, fibrosis Inhibition of inflammation, lipid metabolism, OS, kidney fibrosis ↓MDA, ↑SOD, ↑GSH-Px, ↓α-SMA,
↑SIRT3, ↑SOD2, ↓IL-1β, ↓IL6, ↓TNFα, ↓NF-kB, ↓HMGB1, ↓COX2, ↓c-Jun, ↓c-Fos, ↓SREBP-1c, ↓SCD-1, ↓FASn, ↓p-Akt, ↓p-FoxO1A, ↓ACC, ↑CPT1, ↑Nrf2, ↓Keap1, ↑GST, ↓TGFβ1, ↓p-Smad3, ↑Smad7		 [70]
10 Ergone (alisol B 23-acetate, pachymic acid B) steroid; Polyporus umbellatus, surface layer of Poria cocos, Alisma orientale AngII- treated HK-2 and conditionally immortalized MPC5 cells CKD OS, inflammation, impaired Nrf 2 activation inhibition of the RAS/Wnt/b-catenin signaling cascade (HK-2) ↓Snail1, ↓MMP-7, ↓Twist,
↓FSP-1, ↓Col I, ↓Col III, ↓α-SMA,
↓vimentin, ↑E-cadherin, ↓NF-kB,
↓MCP-1, ↓COX2, ↑Nrf2, ↑HO-1
(podocyte) ↓Snail1, ↓MMP-7, ↓Twist, ↓FSP-1, ↑podocin, ↑nephrin,
↑podocalyxin, ↑synaptopodin,
↓desmin, ↑WT1, ↓Akt2, ↓NF-kB,
↓MCP-1, ↓COX2, ↑Nrf2, ↑HO-1		 [71]
11 L-mimosine Amino acid; Mimosa pudica Rats with remnant kidneys after subtotal nephrectomy (5/6 nephrectomy) CKD Fibrosis Improvement of kidney function, inhibition of fibrosis ↑HIF-1α, ↑HIF-2α, ↑VEGF, ↑HO-1,
↑GLUT-1, ↓α-SMA, ↓collagen III		 [72]
12 Melatonin Endogenous indoleamine, coffee, walnut, etc. Pristine -injected BALB/c mice LN OS, inflammation Attenuation of OS, inflammation ↑SIRT1, ↑Nrf2, ↓TNFα, ↓NF-kB,
↓iNOS, ↓NLRP3, ↑CD31		 [73]
13 Notoginsenoside R1 Saponin; Panax notoginseng db/db mice DKD OS Anti-OS, decrease in apoptosis ↓Collagen I, ↓TGFβ1, ↑Nrf2, ↑HO-1, ↓Bax/Bcl2, ↓Caspase-3, ↓Caspase-9 [74]
AGEs-treated HK-2 cells Mitochondria injury ↓LDH, ↓ROS, ↑n-Nrf2, ↑HO-1,
↓Bax/Bcl2, ↓Cspase-3, ↓Caspase-9, ↓TGFβ1, ↓collagen I
14 Obacunone Triterpenoid limonoid; citrus and other plants of the Rutaceae family HG-treated NRK-52E cells OS OS Inhibition of OS, mitochondrial injury, and apoptosis ↑SOD, ↑GSH, ↑CAT, ↓ROS, ↓JC-1 monomer/aggregate, ↑p-GSK3β/GSK3β, ↓n-Fyn, ↑n-Nrf2, ↑Nqo1, ↑HO-1, ↑SOD, ↑GSH, ↑CAT, ↓c-CytC/m-CytC, ↓cleaved caspase3 [75]
15 Oleanolic acid Triterpenoid; olive oil, Phytolacca Americana, Syzygium spp, garlic, etc. Cyclosporine -treated ICR mice Chronic nephropathy Inflammation, fibrosis Antioxidation, anti-inflammation ↓α-SMA, ↑HO-1, ↑nuclear/total Nrf2, ↑SOD1, ↓MDA, ↓urinary 8-iso-PGF2α, ↓urine 8-oxo-dG, ↓Bax/Bcl2, ↓active caspase-3 [76]
16 Pyrroloquinoline quinone In soil and foods such as kiwifruit and human breast milk HG-treated HK-2 cells OS OS Decrease in OS, inflammation and cellular senescence ↓IL-1β, ↓TNFα, ↓NF-kB, ↓p16,
↓p21, ↓ROS, ↑SOD2, ↑CAT, ↓keap1, ↑Nrf2, ↑HO-1, ↑Nqo1, ↑GST,
↑GPx3,		 [77]
17 Sinomenine Alkaloid; Sinomenium acutum UUO-operated ICR mice CKD Fibrosis, OS Anti-fibrosis, antioxidation ↑E-cadherin, ↓α-SMA, ↓FN,
↑HO-1, ↑Nqo1, ↑Nrf2, ↑SOD, ↑GPx, ↑CAT, ↑SOD2, ↓p-Smad3, ↓β-catenin		 [78]
TGFβ-treated/H2O2-treated HEK293 cells, TGFβ-treated RAW264.7 cells ↑E-cadherin, ↓α-SMA, ↓FN,
↑HO-1, ↑Nqo1, ↑Nrf2, ↑SOD,
↑GPx, ↑CAT, ↑SOD2, ↓p-Smad3, ↓β-catenin
18 Sulforaphane Isothiocyanate (organosulfur compound); Cruciferous vegetables such as broccoli, brussels sprouts, and cabbages STZ-injected and meglumine diatrizoate-injected Wistar rats DKD, CIN OS Renoprotective ↓MDA, ↓8-oxo-dG, ↑Nrf2, ↑HO-1,
↓IL6, ↑Caspase3		 [79][80]
Meglumine diatrizoate-treated NRK-52E cells Cell viability ↑Nrf2, ↑HO-1, ↓IL6
F344 rat kidneys transplanted Lewis rat CRAD OS OS alleviation, kidney functional and morphological improvements ↓MDA, ↓8-isoprostane, ↓ox-LDL, ↓8-oxo-dG, ↑SOD, ↑CAT, ↑GPx, ↑GR, ↑ γ-GCS, ↑Nrf2, ↑HO-1, ↑Nqo-1 [80]
19 Trigonelline Alkaloid; traditional herbs (especially fenugreek), coffee bean, soybean, and other edible food plants Oxalate-induced MDCK cells EMT Fibrosis Attenuation of EMT, prevention of cell migration and ROS overproduction, ↓FN, ↓vimentin, ↓α-SMA,
↑ E-cadherin, ↑ZO-1, ↓MMP9,
↓ROS, ↑Nrf2		 [81]
AGEs, advanced glycation end products; AngII, angiotensin II; α-SMA, α-smooth muscle actin; AT1/2R, angiotensin II receptor type 1/2; CAT, catalase; CIN, contrast induced nephropathy; CKD, chronic kidney disease; COX2, cyclooxygenase 2; CRAD, chronic renal allograft dysfunction; DHE, dihydroethidium; DKD, diabetic kidney disease; EMT, epithelial-to-mesenchymal transition; eNOS, endothelial nitric oxide synthase; FSGS, focal segmental glomerulosclerosis; γ-GCS, γ-glutamine cysteine synthase; GPx, glutathione peroxidase; GR, glutathione reductase; GSK3β, glycogen synthase kinase 3β; GST, Glutathione-S-transferase; HFD, high fat diet; HG, high glucose; HIF, hypoxia-inducible factor; HMGB1, high-mobility group box 1; HO-1, Heme oxygenase-1; iNOS, inducible nitric oxide synthase; LDH, lactate dehydrogenase; LN, lupus nephritis; LPS, lipopolysaccharide; MCP-1, monocyte chemoattractant protein-1; MDA, malondialdehyde; MDCK, Madin-Darby canine kidney; MMP, matrix metalloproteinase; NLRP3, NLR family pyrin domain containing 3; Nqo1, NADPH quinone oxidoreductase; Nrf2, nuclear factor erythroid 2-related factor 2; OS, oxidative stress; ox-LDL, oxidized low-density lipoprotein; RAS, renin-angiotensin system; SOD, superoxide dismutase; STZ, Streptozotocin; UUO, unilateral ureteral obstruction.

This entry is adapted from the peer-reviewed paper 10.3390/antiox10020258

References

  1. Carrero, J.J.; Hecking, M.; Chesnaye, N.C.; Jager, K.J. Sex and gender disparities in the epidemiology and outcomes of chronic kidney disease. Nat. Rev. Nephrol. 2018, 14, 151–164.
  2. Carney, E.F. The impact of chronic kidney disease on global health. Nat. Rev. Nephrol. 2020.
  3. Liu, M.; Li, X.C.; Lu, L.; Cao, Y.; Sun, R.R.; Chen, S.; Zhang, P.Y. Cardiovascular disease and its relationship with chronic kidney disease. Eur. Rev. Med. Pharmacol. Sci. 2014, 18, 2918–2926.
  4. Clausen, P.; Jensen, J.S.; Jensen, G.; Borch-Johnsen, K.; Feldt-Rasmussen, B. Elevated urinary albumin excretion is associated with impaired arterial dilatory capacity in clinically healthy subjects. Circulation 2001, 103, 1869–1874.
  5. Chan, D.T.; Irish, A.B.; Dogra, G.K.; Watts, G.F. Dyslipidaemia and cardiorenal disease: Mechanisms, therapeutic opportunities and clinical trials. Atherosclerosis 2008, 196, 823–834.
  6. Holtkamp, F.A.; De Zeeuw, D.; Thomas, M.C.; Cooper, M.E.; De Graeff, P.A.; Hillege, H.J.L.; Parving, H.H.; Brenner, B.M.; Shahinfar, S.; Heerspink, H.J.L. An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function. Kidney Int. 2011, 80, 282–287.
  7. Wanner, C.; Inzucchi, S.E.; Lachin, J.M.; Fitchett, D.; Von Eynatten, M.; Mattheus, M.; Johansen, O.E.; Woerle, H.J.; Broedl, U.C.; Zinman, B.; et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N. Engl. J. Med. 2016, 375, 323–334.
  8. Gregg, L.P.; Hedayati, S.S. Management of traditional cardiovascular risk factors in CKD: What are the data? Am. J. Kidney Dis. 2018, 72, 728–744.
  9. Cruz, M.C.; Andrade, C.; Urrutia, M.; Draibe, S.; Nogueira-Martins, L.A.; Sesso, R.C.C. Quality of life in patients with chronic kidney disease. Clinics 2011, 66, 991–995.
  10. Lee, H.B.; Yu, M.R.; Yang, Y.; Jiang, Z.; Ha, H. Reactive oxygen species-regulated signaling pathways in diabetic nephropathy. J. Am. Soc. Nephrol. 2003, 14, S241–S245.
  11. Podkowińska, A.; Formanowicz, D. Chronic kidney disease as oxidative stress-and inflammatory-mediated cardiovascular disease. Antioxidants 2020, 9, 752.
  12. Noh, H.; Ha, H. Reactive oxygen species and oxidative stress. In Contributions to Nephrology; Karger: Basel, Switzerland, 2011; Volume 170, pp. 102–112.
  13. Ha, H.; Hwang, I.A.; Park, J.H.; Lee, H.B. Role of reactive oxygen species in the pathogenesis of diabetic nephropathy. Diabetes Res. Clin. Pract. 2008, 82, S42–S45.
  14. Harman, D. The aging process. Proc. Natl. Acad. Sci. USA 1981, 78, 7124.
  15. Kim, J.; Kil, I.S.; Seok, Y.M.; Yang, E.S.; Kim, D.K.; Lim, D.G.; Park, J.W.; Bonventre, J.V.; Park, K.M. Orchiectomy attenuates post-ischemic oxidative stress and ischemia/reperfusion injury in mice. A role for manganese superoxide dismutase. J. Biol. Chem. 2006, 281, 20349–20356.
  16. Stępniewska, J.; Gołembiewska, E.; Dołęgowska, B.; Domański, M.; Ciechanowski, K. Oxidative stress and antioxidative enzyme activities in chronic kidney disease and different types of renal replacement therapy. Curr. Protein Pept. Sci. 2015, 16, 243–248.
  17. Surh, Y.J.; Kundu, J.K.; Na, H.K. Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med. 2008, 74, 1526–1539.
  18. Lv, W.; Booz, G.W.; Fan, F.; Wang, Y.; Roman, R.J. Oxidative stress and renal fibrosis: Recent insights for the development of novel therapeutic strategies. Front. Physiol. 2018, 9, 105.
  19. Chen, D.Q.; Hu, H.H.; Wang, Y.N.; Feng, Y.L.; Cao, G.; Zhao, Y.Y. Natural products for the prevention and treatment of kidney disease. Phytomedicine 2018, 50, 50–60.
  20. Rapa, S.F.; Di Iorio, B.R.; Campiglia, P.; Heidland, A.; Marzocco, S. Inflammation and oxidative stress in chronic kidney disease-potential therapeutic role of minerals, vitamins and plant-derived metabolites. Int. J. Mol. Sci. 2019, 21, 263.
  21. Nezu, M.; Suzuki, N.; Yamamoto, M. Targeting the KEAP1-NRF2 system to prevent kidney disease progression. Am. J. Nephrol. 2017, 45, 473–483.
  22. Lu, M.; Wang, P.; Qiao, Y.; Jiang, C.; Ge, Y.; Flickinger, B.; Malhotra, D.K.; Dworkin, L.D.; Liu, Z.; Gong, R. GSK3β-mediated Keap1-independent regulation of Nrf2 antioxidant response: A molecular rheostat of acute kidney injury to chronic kidney disease transition. Redox Biol. 2019, 26, 101275.
  23. Yamawaki, K.; Kanda, H.; Shimazaki, R. Nrf2 activator for the treatment of kidney diseases. Toxicol. Appl. Pharmacol. 2018, 360, 30–37.
  24. Choi, B.H.; Kang, K.S.; Kwak, M.K. Effect of redox modulating NRF2 activators on chronic kidney disease. Molecules 2014, 19, 12727–12759.
  25. Kanda, H.; Yamawaki, K. Bardoxolone methyl: Drug development for diabetic kidney disease. Clin. Exp. Nephrol. 2020, 24, 857–864.
  26. Abraham, N.G.; Kappas, A. Heme oxygenase and the cardiovascular–renal system. Free Radic. Biol. Med. 2005, 39, 1–25.
  27. Li, S.; Qiu, B.; Lu, H.; Lai, Y.; Liu, J.; Luo, J.; Zhu, F.; Hu, Z.; Zhou, M.; Tian, J.; et al. Hyperhomocysteinemia accelerates acute kidney injury to chronic kidney disease progression by downregulating Heme Oxygenase-1 expression. Antioxid. Redox Signal. 2019, 30, 1635–1650.
  28. Demirogullari, B.; Ekingen, G.; Guz, G.; Bukan, N.; Erdem, O.; Ozen, I.O.; Memis, L.; Sert, S. A comparative study of the effects of hemin and bilirubin on bilateral renal ischemia reperfusion injury. Nephron Exp. Nephrol. 2006, 103, e1–e5.
  29. Chang, T.T.; Chen, Y.A.; Li, S.Y.; Chen, J.W. Nrf-2 mediated heme oxygenase-1 activation contributes to the anti-inflammatory and renal protective effects of Ginkgo biloba extract in diabetic nephropathy. J. Ethnopharmacol. 2020, 266, 113474.
  30. Di Noia, M.A.; Van Driesche, S.; Palmieri, F.; Yang, L.M.; Quan, S.; Goodman, A.I.; Abraham, N.G. Heme oxygenase-1 enhances renal mitochondrial transport carriers and cytochrome C oxidase activity in experimental diabetes. J. Biol. Chem. 2006, 281, 15687–15693.
  31. Bolisetty, S.; Traylor, A.; Zarjou, A.; Johnson, M.S.; Benavides, G.A.; Ricart, K.; Boddu, R.; Moore, R.D.; Landar, A.; Barnes, S.; et al. Mitochondria-targeted heme oxygenase-1 decreases oxidative stress in renal epithelial cells. Am. J. Physiol. Ren. Physiol. 2013, 305, F255–F264.
  32. Kwak, J.Y.; Takeshige, K.; Cheung, B.S.; Minakami, S. Bilirubin inhibits the activation of superoxide-producing NADPH oxidase in a neutrophil cell-free system. Biochim. Biophys. Acta 1991, 1076, 369–373.
  33. Nath, K.A. Heme oxygenase-1: A provenance for cytoprotective pathways in the kidney and other tissues. Kidney Int. 2006, 70, 432–443.
  34. Lever, J.M.; Boddu, R.; George, J.F.; Agarwal, A. Heme oxygenase-1 in kidney health and disease. Antioxid. Redox Signal. 2016, 25, 165–183.
  35. Funes, S.C.; Rios, M.; Fernández-Fierro, A.; Covián, C.; Bueno, S.M.; Riedel, C.A.; Mackern-Oberti, J.P.; Kalergis, A.M. Naturally derived Heme-Oxygenase 1 inducers and their therapeutic application to immune-mediated diseases. Front. Immunol. 2020, 11, 1467.
  36. Dong, C.; Wu, G.; Li, H.; Qiao, Y.; Gao, S. Ampelopsin inhibits high glucose-induced extracellular matrix accumulation and oxidative stress in mesangial cells through activating the Nrf2/HO-1 pathway. Phytother. Res. 2020, 34, 2044–2052.
  37. Zhang, J.; Zhao, X.; Zhu, H.; Wang, J.; Ma, J.; Gu, M. Apigenin protects against renal tubular epithelial cell injury and oxidative stress by high glucose via regulation of NF-E2-related factor 2 (Nrf2) pathway. Med. Sci. Monit. 2019, 25, 5280–5288.
  38. Xie, X.; Chen, Q.; Tao, J. Astaxanthin promotes Nrf2/ARE signaling to inhibit hg-induced renal fibrosis in GMCs. Mar. Drugs 2018, 16, 117.
  39. He, L.; Liu, G.; Shi, Y.; Peng, X.; Liu, H.; Peng, Y. Astaxanthin attenuates adriamycin-induced focal segmental glomerulosclerosis. Pharmacology 2015, 95, 193–200.
  40. Li, D.; Shi, G.; Wang, J.; Zhang, D.; Pan, Y.; Dou, H.; Hou, Y. Baicalein ameliorates pristane-induced lupus nephritis via activating Nrf2/HO-1 in myeloid-derived suppressor cells. Arthritis Res. Ther. 2019, 21.
  41. Elsherbiny, N.M.; Said, E.; Atef, H.; Zaitone, S.A. Renoprotective effect of calycosin in high fat diet-fed/STZ injected rats: Effect on IL-33/ST2 signaling, oxidative stress and fibrosis suppression. Chem. Biol. Interact. 2020, 315.
  42. Bao, L.; Li, J.; Zha, D.; Zhang, L.; Gao, P.; Yao, T.; Wu, X. Chlorogenic acid prevents diabetic nephropathy by inhibiting oxidative stress and inflammation through modulation of the Nrf2/HO-1 and NF-ĸB pathways. Int. Immunopharmacol. 2018, 54, 245–253.
  43. Wang, W.; Wang, X.; Zhang, X.S.; Liang, C.Z. Cryptotanshinone attenuates oxidative stress and inflammation through the regulation of Nrf-2 and NF-κB in mice with unilateral ureteral obstruction. Basic Clin. Pharmacol. Toxicol. 2018, 123, 714–720.
  44. Tapia, E.; García-Arroyo, F.; Silverio, O.; Rodríguez-Alcocer, A.N.; Jiménez-Flores, A.B.; Cristobal, M.; Arellano, A.S.; Soto, V.; Osorio-Alonso, H.; Molina-Jijón, E.; et al. Mycophenolate mofetil and curcumin provide comparable therapeutic benefit in experimental chronic kidney disease: Role of Nrf2-Keap1 and renal dopamine pathways. Free Radic. Res. 2016, 50, 781–792.
  45. Ali, B.H.; Al-Salam, S.; Al Suleimani, Y.; Al Kalbani, J.; Al Bahlani, S.; Ashique, M.; Manoj, P.; Al Dhahli, B.; Al Abri, N.; Naser, H.T.; et al. Curcumin ameliorates kidney function and oxidative stress in experimental chronic kidney disease. Basic Clin. Pharmacol. Toxicol. 2018, 122, 65–73.
  46. Zhang, X.; Liang, D.; Guo, L.; Liang, W.; Jiang, Y.; Li, H.; Zhao, Y.; Lu, S.; Chi, Z.H. Curcumin protects renal tubular epithelial cells from high glucose-induced epithelial-to-mesenchymal transition through Nrf2-mediated upregulation of heme oxygenase-1. Mol. Med. Rep. 2015, 12, 1347–1355.
  47. Sun, W.; Liu, X.; Zhang, H.; Song, Y.; Li, T.; Liu, X.; Liu, Y.; Guo, L.; Wang, F.; Yang, T.; et al. Epigallocatechin gallate upregulates NRF2 to prevent diabetic nephropathy via disabling KEAP1. Free Radic. Biol. Med. 2017, 108, 840–857.
  48. Tsai, P.Y.; Ka, S.M.; Chang, J.M.; Chen, H.C.; Shui, H.A.; Li, C.Y.; Hua, K.F.; Chang, W.L.; Huang, J.J.; Yang, S.S.; et al. Epigallocatechin-3-gallate prevents lupus nephritis development in mice via enhancing the Nrf2 antioxidant pathway and inhibiting NLRP3 inflammasome activation. Free Radic. Biol. Med. 2011, 51, 744–754.
  49. Wang, Y.; Wang, B.; Du, F.; Su, X.; Sun, G.; Zhou, G.; Bian, X.; Liu, N. Epigallocatechin-3-Gallate attenuates oxidative stress and inflammation in obstructive nephropathy via NF-κB and Nrf2/HO-1 signalling pathway regulation. Basic Clin. Pharmacol. Toxicol. 2015, 117, 164–172.
  50. An, L.; Zhou, M.; Marikar, F.M.M.T.; Hu, X.W.; Miao, Q.Y.; Li, P.; Chen, J. Salvia miltiorrhiza lipophilic fraction attenuates oxidative stress in diabetic nephropathy through activation of nuclear factor erythroid 2-related factor 2. Am. J. Chin. Med. 2017, 45, 1441–1457.
  51. Liu, Y.; Xu, X.; Xu, R.; Zhang, S. Renoprotective effects of isoliquiritin against cationic bovine serum albumin-induced membranous glomerulonephritis in experimental rat model through its anti-oxidative and anti- inflammatory properties. Drug Des. Dev. Ther. 2019, 13, 3735–3751.
  52. Castejon, M.L.; Sánchez-Hidalgo, M.; Aparicio-Soto, M.; Montoya, T.; Martín-LaCave, I.; Fernández-Bolaños, J.G.; Alarcón-de-la-Lastra, C. Dietary oleuropein and its new acyl-derivate attenuate murine lupus nephritis through HO-1/Nrf2 activation and suppressing JAK/STAT, NF-κB, MAPK and NLRP3 inflammasome signaling pathways. J. Nutr. Biochem. 2019, 74.
  53. Huang, T.; Dong, Z. Osthole protects against inflammation in a rat model of chronic kidney failure via suppression of nuclear factor-κB, transforming growth factor-β1 and activation of phosphoinositide 3-kinase/protein kinase B/nuclear factor (erythroid-derived 2)-like 2 signaling. Mol. Med. Rep. 2017, 16, 4915–4921.
  54. Koca, H.B.; Pektas, M.B.; Koca, S.; Pektas, G.; Sadi, G. Diabetes-induced renal failure is associated with tissue inflammation and neutrophil gelatinase-associated lipocalin: Effects of resveratrol. Arch. Biol. Sci. 2016, 68, 747–752.
  55. Bae, E.H.; Joo, S.Y.; Ma, S.K.; Lee, J.U.; Kim, S.W. Resveratrol attenuates 4-hydroxy-2-hexenal-induced oxidative stress in mouse cortical collecting duct cells. Korean J. Physiol. Pharmacol. 2016, 20, 229–236.
  56. Sun, Y.; Zhang, Y.; Zhao, D.; Ding, G.; Huang, S.; Zhang, A.; Jia, Z. Rotenone remarkably attenuates oxidative stress, inflammation, and fibrosis in chronic obstructive uropathy. Mediat. Inflamm. 2014, 2014.
  57. Lu, H.; Li, Y.; Zhang, T.; Liu, M.; Chi, Y.; Liu, S.; Shi, Y. Salidroside reduces high-glucose-induced podocyte apoptosis and oxidative stress via upregulating heme oxygenase-1 (HO-1) expression. Med. Sci. Monit. 2017, 23, 4067–4076.
  58. Wu, P.; Yan, Y.; Ma, L.L.; Hou, B.Y.; He, Y.Y.; Zhang, L.; Niu, Z.R.; Song, J.K.; Pang, X.C.; Yang, X.Y.; et al. Effects of the Nrf2 protein modulator salvianolic acid a alone or combined with metformin on diabetes-associated macrovascular and renal injury. J. Biol. Chem. 2016, 291, 22288–22301.
  59. Wang, J.H.; Zhang, H.F.; Wang, J.H.; Wang, Y.L.; Gao, C.; Gu, Y.T.; Huang, J.; Zhang, Z. Salvianolic acid A protects the kidney against oxidative stress by activating the Akt/GSK-3 β /Nrf2 signaling pathway and inhibiting the NF- B signaling pathway in 5/6 nephrectomized rats. Oxidative Med. Cell. Longev. 2019, 2019.
  60. Prabu, S.M.; Muthumani, M. Silibinin ameliorates arsenic induced nephrotoxicity by abrogation of oxidative stress, inflammation and apoptosis in rats. Mol. Biol. Rep. 2012, 39, 11201–11216.
  61. Alaofi, A.L. Sinapic acid ameliorates the progression of streptozotocin (STZ)-induced diabetic nephropathy in rats via NRF2/HO-1 mediated pathways. Front. Pharmacol. 2020, 11.
  62. Lu, C.; Fan, G.; Wang, D. Akebia Saponin D ameliorated kidney injury and exerted anti-inflammatory and anti-apoptotic effects in diabetic nephropathy by activation of NRF2/HO-1 and inhibition of NF-KB pathway. Int. Immunopharmacol. 2020, 84.
  63. García Trejo, E.M.Á.; Buendía, A.S.A.; Reyes, O.S.; Arroyo, F.E.G.; García, R.A.; Mendoza, M.L.L.; Tapia, E.; Lozada, L.G.S.; Alonso, H.O. The beneficial effects of Allicin in chronic kidney disease are comparable to Losartan. Int. J. Mol. Sci. 2017, 18, 1980.
  64. Tsai, P.Y.; Ka, S.M.; Chao, T.K.; Chang, J.M.; Lin, S.H.; Li, C.Y.; Kuo, M.T.; Chen, P.; Chen, A. Antroquinonol reduces oxidative stress by enhancing the Nrf2 signaling pathway and inhibits inflammation and sclerosis in focal segmental glomerulosclerosis mice. Free Radic. Biol. Med. 2011, 50, 1503–1516.
  65. Zhang, H.; Qi, S.; Song, Y.; Ling, C. Artemisinin attenuates early renal damage on diabetic nephropathy rats through suppressing TGF-β1 regulator and activating the Nrf2 signaling pathway. Life Sci. 2020, 256.
  66. Ma, B.; Zhu, Z.; Zhang, J.; Ren, C.; Zhang, Q. Aucubin alleviates diabetic nephropathy by inhibiting NF-κB activation and inducing SIRT1/SIRT3-FOXO3a signaling pathway in high-fat diet/streptozotocin-induced diabetic mice. J. Funct. Foods 2020, 64.
  67. Zhang, X.; He, H.; Liang, D.; Jiang, Y.; Liang, W.; Chi, Z.H.; Ma, J. Protective effects of berberine on renal injury in streptozotocin (STZ)-Induced diabetic mice. Int. J. Mol. Sci. 2016, 17, 1327.
  68. Xie, R.; Zhang, H.; Wang, X.Z.; Yang, X.Z.; Wu, S.N.; Wang, H.G.; Shen, P.; Ma, T.H. The protective effect of betulinic acid (BA) diabetic nephropathy on streptozotocin (STZ)-induced diabetic rats. Food Funct. 2017, 8, 299–306.
  69. Yang, S.M.; Hua, K.F.; Lin, Y.C.; Chen, A.; Chang, J.M.; Kuoping Chao, L.; Ho, C.L.; Ka, S.M. Citral is renoprotective for focal segmental glomerulosclerosis by inhibiting oxidative stress and apoptosis and activating Nrf2 pathway in mice. PLoS ONE 2013, 8, e74871.
  70. Qiao, Y.; Xu, L.; Tao, X.; Yin, L.; Qi, Y.; Xu, Y.; Han, X.; Tang, Z.; Ma, X.; Liu, K.; et al. Protective effects of dioscin against fructose-induced renal damage via adjusting Sirt3-mediated oxidative stress, fibrosis, lipid metabolism and inflammation. Toxicol. Lett. 2018, 284, 37–45.
  71. Chen, L.; Chen, D.Q.; Wang, M.; Liu, D.; Chen, H.; Dou, F.; Vaziri, N.D.; Zhao, Y.Y. Role of RAS/Wnt/β-catenin axis activation in the pathogenesis of podocyte injury and tubulo-interstitial nephropathy. Chem. Biol. Interact. 2017, 273, 56–72.
  72. Yu, X.; Fang, Y.; Ding, X.; Liu, H.; Zhu, J.; Zou, J.; Xu, X.; Zhong, Y. Transient hypoxia-inducible factor activation in rat renal ablation and reduced fibrosis with L-mimosine. Nephrology 2012, 17, 58–67.
  73. Bonomini, F.; Dos Santos, M.; Veronese, F.V.; Rezzani, R. NLRP3 inflammasome modulation by melatonin supplementation in chronic pristane-induced lupus nephritis. Int. J. Mol. Sci. 2019, 20, 3466.
  74. Zhang, B.; Zhang, X.; Zhang, C.; Shen, Q.; Sun, G.; Sun, X. Notoginsenoside R1 protects db/db mice against diabetic nephropathy via upregulation of Nrf2-mediated HO-1 expression. Molecules 2019, 24, 247.
  75. Zhou, J.; Wang, T.; Wang, H.; Jiang, Y.; Peng, S. Obacunone attenuates high glucose-induced oxidative damage in NRK-52E cells by inhibiting the activity of GSK-3β. Biochem. Biophys. Res. Commun. 2019, 513, 226–233.
  76. Hong, Y.A.; Lim, J.H.; Kim, M.Y.; Kim, E.N.; Koh, E.S.; Shin, S.J.; Choi, B.S.; Park, C.W.; Chang, Y.S.; Chung, S. Delayed treatment with oleanolic acid attenuates tubulointerstitial fibrosis in chronic cyclosporine nephropathy through Nrf2/HO-1 signaling. J. Transl. Med. 2014, 12.
  77. Wang, Z.; Han, N.; Zhao, K.; Li, Y.; Chi, Y.; Wang, B. Protective effects of pyrroloquinoline quinine against oxidative stress-induced cellular senescence and inflammation in human renal tubular epithelial cells via Keap1/Nrf2 signaling pathway. Int. Immunopharmacol. 2019, 72, 445–453.
  78. Qin, T.; Yin, S.; Yang, J.; Zhang, Q.; Liu, Y.; Huang, F.; Cao, W. Sinomenine attenuates renal fibrosis through Nrf2-mediated inhibition of oxidative stress and TGFβ signaling. Toxicol. Appl. Pharmacol. 2016, 304, 1–8.
  79. Khaleel, S.A.; Raslan, N.A.; Alzokaky, A.A.; Ewees, M.G.; Ashour, A.A.; Abdel-Hamied, H.E.; Abd-Allah, A.R. Contrast media (meglumine diatrizoate) aggravates renal inflammation, oxidative DNA damage and apoptosis in diabetic rats which is restored by sulforaphane through Nrf2/HO-1 reactivation. Chem. Biol. Interact. 2019, 309.
  80. Lv, D.; Zhou, Q.; Xia, Y.; You, X.; Zhao, Z.; Li, Y.; Zou, H. The association between oxidative stress alleviation via sulforaphane-induced Nrf2-HO-1/NQO-1 signaling pathway activation and chronic renal allograft dysfunction improvement. Kidney Blood Press. Res. 2018, 43, 191–205.
  81. Peerapen, P.; Thongboonkerd, V. Protective roles of trigonelline against oxalate-induced epithelial-to-mesenchymal transition in renal tubular epithelial cells: An in vitro study. Food Chem. Toxicol. 2020, 135.
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