Small Molecule Natural Products Targeting Nrf2-HO-1 Signaling: Comparison
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Please note this is a comparison between Version 1 by Md Jamal Uddin and Version 2 by Vivi Li.

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][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][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][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][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][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][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][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, rwesearchers 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 13. To facilitate the discussion, rwesearchers 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.
Antioxidants 10 00258 g003 550
Figure 13. 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.
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.
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][109]
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][133]
2 Apigenin Flavonoid; common fruits and vegetables HG-treated HK-2 cells Oxidative damage Oxidative damage
HG-treated HK-2 cellsDecrease in apoptosis, inhibition of OS, and inflammatory response ↓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		↓LDH, ↓MDA, ↑SOD, ↑CAT, ↓TNFα, ↓IL-1β, ↓IL-6, ↑Nrf2, ↑HO-1 [37][110]
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
2 Allicin Diallyl thiosulfinate; garlic (Allium sativum L.)] 5/6 nephrectomy Wistar rat[ CKD Fibrosis, OS111 Antihypertensive and antioxidant effects]
↑AT1R, ↑AT2R, ↑Nrf2, ↓Keap1,

↑CAT, ↑SOD, ↓HO-1, ↑eNOS [63][134] HG-treated GMCs Kidney fibrosis OS
3Increase in antioxidative capacity Antroquinonol↓FN, ↓TGFβ1, ↓ICAM-1, ↑SOD, Enone; mushroom (Antrodia camphorate)

↓MDA, ↓ROS, ↓DHE, ↑n-Nrf2,

↓keap1, ↓SOD-1, ↓Nqo1, ↓HO-1
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][135] Adriamycin-treated BALB/c mice
4FSGS OS, inflammation Anti-inflammation, antioxidation ↓TGFβ1, ↓collagen1, ↓α-SMA, ↓MDA, ↑GSH, ↑SOD, ↑CAT, (serum: ↓IL-1 β, IL-18), ↑Nrf2, ↓NLRP3 Artemisinin[39 sesquiterpene lactones; Asteraceae Artemisia annua STZ-injected rat] DKD[112]
OS Amelioration of kidney dysfunction and OS ↓MDA, ↑t-SOD, ↑GPx, ↓TGFβ1, ↑t-Nrf2, ↑n-Nrf2, ↑HO-1, ↑Nqo1 [65][136] 4 Baicalein Flavonoid; roots of Scutellaria baicalensis Georgi Pristine -injected BALB/c mice LN OS, inflammation
5 Aucubin iridoid glycoside; leaf of Attenuation of kidney dysfunction, antioxidation, anti-inflammation, inhibition of MDSC expansion Eucommia ulmoides↓IL-1b, ↓IL-18, ↓O2¯˙,

↑ GPx, ↑Nrf2, ↑HO-1, ↓ NLRP3,

↓Casp-1, ↓mIL-1 β, ↓p-NF-kB		 HFD-fed and STZ-injected mice[ DKD40 OS, inflammation][113]
Amelioration of kidney dysfunction, anti-inflammation, anti-OS 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
↓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, 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][114]
6 7Chlorogenic acid Cinnamate ester; coffee, fruits, and vegetables STZ-injected and HFD-fed SD rat DKD Betulinic acid pentacyclic triterpenoid; from the outer bark of white birch trees (Betula alba)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][115]
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][139] 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
8 Citral Terpeonids; Litsea cubeba Adriamycin -injected BALB/c mice FSGS 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][116]
8
↑SOD, ↑CAT, ↑GSH-Px, ↓MPO,

↓TNFα, ↓IL-6, ↓IL-1 β, ↑IkBα, ↓p-IkBα, ↓NF-kB, ↑n-Nrf2, ↑HO-1, ↑t-bilirubin [49][121]


↓Ac-FOXO3α/FOXO3α [66][137] 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][140]
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		 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][122]
HG-treated SV40-MES-13 MMCs
[
59
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][138 hyperglycemia Antioxidation ↓ROS, ↑Nrf2, ↑HO-1, ↑Nqo1,

↓Keap1
]
HG-treated NRK 52E cells EMT ↓E-cadherin, ↓α-SMA, ↑n-Nrf2,

↑Nqo1, ↑HO-1, ↓p-Smad2, ↓p-Smad3		 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][117]
[70][141] 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
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[45][118]
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][142] HG-treated NRK-52E cells OS OS Increase in cell viability, inhibition of EMT
11 L-mimosine Amino acid; ↑E-cadherin, ↓α-SMA, ↑Nrf2, ↑HO-1 Mimosa pudica[46][119]
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][143] 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 [
12 Melatonin Endogenous indoleamine, coffee, walnut, etc. Pristine -injected BALB/c mice47 LN OS, inflammation Attenuation of OS, inflammation ↑SIRT1, ↑Nrf2, ↓TNFα, ↓NF-kB,

↓iNOS, ↓NLRP3, ↑CD31		][120]
[73][144] HG-cultured MMC ↑t-Nrf2, ↑c-Nrf2, ↑n-Nrf2, ↑Nqo1, ↑HO-1, ↓MDA, ↓iNOS, ↓VCAM-1,

↓ICAM-1, ↓COL4, ↓FN
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][145] NZB/W F1 lupus-prone mice LN OS Antioxidant and anti-inflammation
AGEs-treated HK-2 cells Mitochondria injury ↓LDH, ↓ROS, ↑n-Nrf2, ↑HO-1,↑Nrf2, ↓p47phox, ↑Nqo1, ↑HO-1, ↑GPx, ↓CD3, ↓F4/80, ↓NF-kB,

↓NLRP3, ↓IL-1 β, ↓IL-18, ↓casp1-p20,

[48][56]
↓Bax/Bcl2, ↓Cspase-3, ↓Caspase-9, ↓TGFβ1, ↓collagen I UUO mice CKD OS, inflammation
14 ObacunoneKidney function improvement, prevention of OS and inflammation 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][146]
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][147]
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][148] 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 [
17 Sinomenine Alkaloid; Sinomenium acutum UUO-operated ICR mice CKD Fibrosis, OS51 Anti-fibrosis, antioxidation ↑E-cadherin, ↓α-SMA, ↓FN,

↑HO-1, ↑Nqo1, ↑Nrf2, ↑SOD, ↑GPx, ↑CAT, ↑SOD2, ↓p-Smad3, ↓β-catenin][54]
[78][149] 12
TGFβ-treated/HOleuropein, peracetylatedoleuropein 2Secoiridoid; olive leaves, roots, and unprocessed olive drupes O2Pristine -injected BALB/c mice -treated HEK293 cells, TGFβ-treated RAW264.7 cells ↑E-cadherin, ↓α-SMA, ↓FN,

↑HO-1, ↑Nqo1, ↑Nrf2, ↑SOD,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][123]
↑GPx, ↑CAT, ↑SOD2, ↓p-Smad3, ↓β-catenin 13 Osthole Coumarin; Fructus Cnidii
182% adenine suspension -received rat CKD SulforaphaneInflammation Protection of kidney function, antiinflammation ↓TNFα, ↓IL-6, ↓IL-8, ↓NF-kB/p65, Isothiocyanate (organosulfur compound); Cruciferous vegetables such as broccoli, brussels sprouts, and cabbages STZ-injected and meglumine diatrizoate-injected Wistar rats DKD, CIN OS

↓TGFβ1, ↓MCP-1, ↑p-Akt/Akt, ↑Nrf2		 Renoprotective ↓MDA, ↓8-oxo-dG, ↑Nrf2, ↑HO-1,

↓IL6, ↑Caspase3[53][124]
[79][80][150,151] 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		  
Meglumine diatrizoate-treated NRK-52E cells Cell viability ↑Nrf2, ↑HO-1, ↓IL6 HG-treated rat GMCs ↑Nrf2, ↓Keap1, ↑n-Nrf2, ↓n-CKIP-1, ↑ARE binding activity, ↑HO-1, ↑SOD1, ↓DHE, ↓H2O2, ↓FN, ↓ICAM-1
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][151] 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
19 Trigonelline][125]
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][152 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][126]
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][127]
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][128]
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][129]
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 ][130]
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][131]
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][132]
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.
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