Small Molecule Natural Products Targeting Nrf2-HO-1 Signaling

Small Molecule Natural Products Targeting Nrf2-HO-1 Signaling: Comparison

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.

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]
1	Akebia Saponin D	triterpenoid saponin; Dipsaci Radix	2	DKD	OS, inflammation		Apigenin	^[62][133]	Flavonoid; common fruits and vegetables	HG-treated HK-2 cells	Oxidative damage	Oxidative damage
HG-treated HK-2 cells	Decrease 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	^[38	[	CKD	Fibrosis, OS	111	Antihypertensive and antioxidant effects	]
			↑AT1R, ↑AT2R, ↑Nrf2, ↓Keap1,		↑CAT, ↑SOD, ↓HO-1, ↑eNOS	^]	^[	⁶³	[	^]	[	111	134	]	]	HG-treated GMCs	Kidney fibrosis	OS
3	Increase 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, ↓O	₂	^●−	, (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
4	FSGS	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, ↓O	₂	^¯˙, ↑ GPx, ↑Nrf2, ↑HO-1, ↓ NLRP3, ↓Casp-1, ↓mIL-1 β, ↓p-NF-kB	HFD-fed and STZ-injected mice	4	Baicalein	Flavonoid; roots of Scutellaria baicalensis Georgi	^[	DKD	OS, inflammation	⁴⁰	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								^[			⁴⁰		^][113]
↓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	7	Chlorogenic 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]
6	STZ-injected SD rat	Chlorogenic acid	Cinnamate ester; coffee, fruits, and vegetables	DKD	DKD	OS	Anti-OS	OS, inflammation	↓IL-1 β, ↓IL-6, ↓MDA, ↑SOD, ↑CAT, ↑p-AMPK/AMPK, ↓p-IkBα/IkBα, ↓p-NF-kB/NF-kB, ↑Nrf2, ↑HO-1	^[	^[42][115]	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	Citral	Terpeonids; Litsea cubeba	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)							OS			^[69][140]
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								10	Ethyl acetate extract of Saliva miltiorrhiza				Oxidative stress			^[50][122]
^[
^[	⁵⁹
6	⁵⁹	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
6	]	Berberine				OS	Anti-fibrosis		^[67][138
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 mice	⁴⁷	LN	OS, inflammation	Attenuation of OS, inflammation	↑SIRT1, ↑Nrf2, ↓TNFα, ↓NF-kB, ↓iNOS, ↓NLRP3, ↑CD31				^][120]	DKD	Oxidative damage, inflammation,	Anti-OS		^[
^[	⁷³	^]	[	⁴⁷	144	]	HG-cultured MMC	↑t-Nrf2, ↑c-Nrf2, ↑n-Nrf2, ↑Nqo1, ↑HO-1, ↓MDA, ↓iNOS, ↓VCAM-1, ↓ICAM-1, ↓COL4, ↓FN				^][120]
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
13	Notoginsenoside R1	Saponin; Panax notoginseng	AGEs-treated HK-2 cells	Mitochondria injury	OS	Anti-OS, decrease in apoptosis	↓LDH, ↓ROS, ↑n-Nrf2, ↑HO-1,	^[74][145]	↑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	Obacunone	Kidney 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, OS	⁵¹	Anti-fibrosis, antioxidation	↑E-cadherin, ↓α-SMA, ↓FN, ↑HO-1, ↑Nqo1, ↑Nrf2, ↑SOD, ↑GPx, ↑CAT, ↑SOD2, ↓p-Smad3, ↓β-catenin^][54]
17	Sinomenine	Alkaloid; Sinomenium acutum	^[	CKD	Fibrosis, OS	⁷⁸	Anti-fibrosis, antioxidation	^]	[	149	]	12
TGFβ-treated/H	Oleuropein, peracetylatedoleuropein	₂Secoiridoid; olive leaves, roots, and unprocessed olive drupes	^[	O₂Pristine -injected BALB/c mice	-treated HEK293 cells, TGFβ-treated RAW264.7 cells	⁷⁸	↑E-cadherin, ↓α-SMA, ↓FN, ↑HO-1, ↑Nqo1, ↑Nrf2, ↑SOD,LN	^]	[	149	]	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
18	2% adenine suspension -received rat	CKD	Sulforaphane	Inflammation	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		^]	DKD, CIN	OS	[	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
	^[	⁷⁹		^]	^[	⁸⁰		^]	Meglumine diatrizoate-treated NRK-52E cells	Cell viability	[	150	,151]	14	Polydatin	Stilbenoid glucoside; Polygonum cuspidatum Sieb.et Zucc	↑Nrf2, ↑HO-1, ↓IL6	DKD	OS	Improvement of antioxidative effect and kidney dysfunction	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	]	15	Resveratrol				OS	Anti-inflammation, Anti-OS
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	DKD	OS	Anti-OS	↑HO-1, ↓α-SMA, ↓p65, ↓ROS	^[58][129]
			]	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	CKD	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		^][130]
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.