Table 1.

Plant-derived extracts and compounds having nephroprotective effects against renal ischemic reperfusion injury-induced acute kidney injury.

Substance used	Source	Experimental model	Ischemia	Mechanism	Route of Administration and order	Effects	Reference
(−)-α-Bisabolol	Matricaria chamomilla, M. crassifolium, Salvia runcinata, Vanillosmopsis sp.	Male Wistar albino rat (in vivo) LLC-MK 2 cells (in vitro)	Right renal nephrectomy and left kidney ischemia for 60 min followed by 48 h reperfusion	Antioxidant, anti-inflammatory, antiapoptotic	Oral route posttreatment	↓Urine osmolality ↓SCr, urea, uric acid, MDA ↓FENa+, FEK+, FECl− ↓uKim-1, ↓Proteinuria, Albuminuria ↓Renal histopathological score ↑Creatinine clearance, GSH ↑Water consumption, diuresis ↑Cell viability	[26]
	Various plants and herbs, e.g., in essential oil of Matricaria chamomilla	HK2 cells	In vitro ischemic reperfusion model by the anaerobic chamber method. Firstly, ischemia was induced for 24 h followed by 3 h reperfusion.	Antioxidant, antiapoptotic	Posttreatment	↓Cell apoptosis ↓TBARS ↓KIM-1 ↑Cell viability ↑GSH Inhibit NADPH oxidase 4	[111]
Acai fruit extract	Euterpe oleracea	Male Wistar albino rat	Bilateral ischemia for 45 min followed by 6 h reperfusion	Antioxidant, antiinflammatory	Oral route pretreatment	↓SCr, BUN, renal KIM-1 ↓MDA, MPO, IFN-γ, caspase-3 ↓Collagen IV, endothelin-1 ↑IL-10	[112]
Aloperine	Sophora alopecuroides	C57BL/6 mice RAW264.7 and HK2 cells	Bilateral ischemia for 45 min followed by 24 h reperfusion	By regulating PI3K/Akt/mTOR signaling and NF-κB transcriptional activity		↓IFN-ϒ, IL-1β, caspase-3 ↓NF-κB expression (in-vitro & in-vivo) ↓PI3K/AkT/mTOR pathway signaling ↑IL-10, SOD	[113]
Apigenin	Celery parsley wheat sprouts	Male Sprague Dawley rat NRK-52E cells	Bilateral ischemia for 45 min followed by 24 h reperfusion	Activation of the JAK2/STAT3 pathway	Intraperitoneal route pretreatment	↓SCr, BUN, MDA ↑SOD and GPx levels in vivo and in vitro ↑JAK2 and STAT3 phosphorylation in vivo and in vitro ↑Bcl-2 and procaspase-3 expression ↓Bax and caspase-3 expression	[114]
Aqueous extract	Cuscuta chinensis (seeds)	Male Sprague Dawley rat	Bilateral ischemia for 45 min followed by 4 days reperfusion	By upregulation of water channels and Na+K+ ATPase	Oral route Posttreatment	↓Urine volume ↑Urine osmolality ↑Urinary Na+, K+, Cl− ↑Creatinine clearance ↑AQP-2, AQP-3 expression ↑Na+K+ ATPase	[115]
Aqueous extract	Murraya koenigii (leaves)	Male Wistar albino rat	Unilateral ischemia in the left kidney for 60 minutes followed by reperfusion	Antioxidant	Oral route pretreatment and posttreatment	↓SCr, BUN, MDA, MPO ↓Proteinuria ↑SOD, CAT, GSH	[116]
Arctigenin	Arctium lappa (fruit)	Male C57BL/6 mice	Bilateral ischemia for 30 min followed by 24 h reperfusion	Anti-inflammatory effect	Oral route pretreatment	↓IL-1β, IL-6, TNF-α ↓IL-10 ↓TLR4/Myd88 protein expression ↓NF-κB expression	[117]
Ascorbic acid	Potatoes, green leafy vegetables, root vegetables, citrus fruits etc.	Male Sprague Dawley rat	Right nephrectomy with left renal ischemia for 45 min followed by 3 h reperfusion	Inhibiting oxidative stress	Intraperitoneal route pretreatment	↓SCr, BUN, LDH, MDA ↓Renal histopathological score ↑GSH	[118, 119]
Berberine	Berberis vulgaris, Hydrastis canadensis, Coptis chinensis, Arcangelisia flava, B. aquifolium, B. aristata	Male Wistar albino rat	Right renal nephrectomy and left kidney ischemia for 45 min followed by 4 weeks reperfusion	Nephroprotection by caspase mitochondria dependent pathway	Oral route posttreatment	↓SCr, BUN, MDA, MPO ↓Na-K-ATPase and Ca-ATPase ↓KIM-1 and TNF-α mRNA expression ↓Bax, ↓Caspase-3 mRNA expression ↑Renal SOD and GSH ↑Bcl2 mRNA expression	[30]
Betulinic acid	Betula alba (bark)		Right nephrectomy with left renal ischemia for 45 min followed by 6 h reperfusion	Inhibit leukocyte apoptosis and upregulation of Na+K+ ATPase	Intraperitoneal route pretreatment	↓SCr, BUN, LDH, MDA ↓TNF-α, MPO ↓Leukocyte apoptosis ↑Na+K+ ATPase, GSH	[120]
Caffeic acid	Commonly found in grains, fruits, and dietary add-ons as simple esters with quinic acid or saccharides		Bilateral ischemia reperfusion for 90 minutes followed by reperfusion for 24 hours	Inhibit 5-lipoxygenase pathway. Anti-inflammatory and antioxidant effect	Oral route pretreatment	↓SCr, BUN, MDA, ↓TNF α ↑Catalase, SOD	[121]
Cannabidiol	Cannabis sativa	Male Sprague Dawley rat	Bilateral ischemia for 30 min followed by 24 h reperfusion	Antioxidant, anti-inflammatory, antiapoptotic activity	Intravenous pre- and posttreatment	↓SC, MDA, NO ↓iNOS, TNF-α, COX-2 ↓ NF-κB, FasL caspase-3 ↑GSH	[122]
Curcumin	Curcuma longa	Male Wistar albino rat	Bilateral ischemia for 45 min followed by 24 h days reperfusion	Antioxidant, free radical scavenging	Oral route pretreatment	↓SCr, BUN, cystatin C ↓MDA, NO ↓Total oxidant status ↑SOD, GPx (serum and renal) ↑Catalase (renal) ↑Total antioxidant capacity	[123]
Dioscin	Dioscorea nipponica	Male Sprague Dawley rat NRK-52E and the HK-2 cells	Bilateral kidney ischemia for 45 min followed by 24 h reperfusion	Inhibiting theTLR4/MyD88 signaling pathway via upregulation of HSP70		↓SCr, BUN ↓TLR4, MyD88, TRAF6 in vitro and in vivo ↓IL-1, IL-6, TNF-α, ICAM-1 ↓IFN-ϒ in vitro and in vivo ↑HSP 70 in vitro and in vivo ↑Cell viability	[124]
Epigallocatechin gallate	Camellia sinensis	Male Sprague Dawley rat	Right nephrectomy and left kidney ischemia for 45 min followed by 24 h reperfusion	Anti-inflammatory suppressing NF-κB decreasing apoptosis	Intraperitoneal route pretreatment	↓SCr, BUN ↓TNF-α, IL-6, IL-1β ↓Cleavage caspase-3 and Bax ↑Caspase-3 and BCL-2 Suppressing NF-κB	[125]
Ethanolic extract	Apium graveolens (leaves and stem)		Bilateral ischemia for 45 min followed by reperfusion	Antioxidant and anti-inflammatory	Oral route pretreatment and posttreatment	↓SCr, urea ↑SOD and nitrogen oxide level	[126]
	Crateva nurvala (leaves and bark)	Male Wistar albino rat	Unilateral ischemia for 1 hour followed by 24 h reperfusion	Antioxidant and anti-inflammatory	Oral route pretreatment	↓SCr, BUN, LDH, MDA ↑NR-F2, GSH ↓TNF-α, IL-6, caspase-3	[27]
	Sonchus oleraceus		Bilateral ischemia for 45 min followed by 15 h reperfusion	Antioxidant and anti-inflammatory	Pretreatment	↓SCr, BUN, MDA ↑SOD ↓IL-6, IL-1β, TNF-α	[110]
	Brassica rapa (roots)		Bilateral ischemia for 60 min followed by 24 h reperfusion	Anti-inflammatory antioxidant		↓SCr, urea, uric acid ↓Renal tissue hemorrhage ↓Necrosis and tubular distention	[127]
	Hypericum perforatum (flowering herb)	Male Sprague Dawley rat	Left renal ischemia for 45 min with right renal nephrectomy followed by 3 h reperfusion	Antioxidant and anti-inflammatory	Intraperitoneal route pretreatment	↓SCr, BUN, MDA ↑SOD, catalase, GPx	[105]
	Petroselinum cripum	Male Wistar albino rat	Bilateral renal ischemia for 30 min followed by reperfusion for 24 hours	Attenuating oxidative stress and inflammation		↓SCr, BUN, MDA, ↓NO, ICAM-1, TNF-α ↓Leukocyte infiltration rate ↑Glomerulus dimeter, FRAP level	[128]
	Salvia miltiorrhiza		Bilateral ischemia for 60 min followed by 30 min reperfusion	Antioxidant anti-inflammatory	Oral route pretreatment	↓SCr, BUN, MDA ↓IL-6, IL-8, TNF-α ↑GSH, SOD, catalase, GPx	[129]
	Tribulus terrestris	Male Sprague Dawley rat	Bilateral ischemia for 30 min followed by 24 h reperfusion	Antioxidant		↓SCr, BUN, MDA ↓Na+, K+ excretion, FRAP ↑Urine osmolality, ↑Creatinine clearance	[130]
	Dalbergia ecastaphyllum	Male Wistar albino rats	Right nephrectomy and left kidney ischemia for 60 min followed by 48 h reperfusion	By reducing oxidative stress, eNOS, and heme-oxygenase upregulation		↓SCr, serum urea ↓Renal and urine MDA, GSH Restores eNOS expression ↑Heme-oxygenase expression	[131]
Ferulic acid	Commelinid plants, grasses, grains, vegetables, flowers, fruits, leaves, beans, seeds of coffee, artichoke, peanut, and nuts	Male C57/BL6 mice	Bilateral ischemia for 35 min followed by 24 h reperfusion	Increasing adenosine generation via HIF-1α	Oral route pretreatment	↓SCr, BUN, caspase-3 ↓IL-1β, TNF-α, MPO activity ↑Adnesine activity ↑CD 73, CD 39 ↑HIF-1α mRNA	[132]
Garlic juice	Allium sativum (bulbs)	Male Wistar albino rats	Right nephrectomy with left renal ischemia for 45 min followed by 24 h reperfusion	Antioxidant, antiapoptotic		↓SC, urea, FENa+, FEK+ ↓Renal histopathological score ↑Urinary creatinine	[133]
Garlic oil			Bilateral ischemia for 45 min followed by 6 h days reperfusion	Antioxidant, anti-inflammatory		↓SC, Urea, Cystatin C ↓Oxidative stress index ↓MPO, NO	[134]
Ginger	Zingiber officinale		Right nephrectomy with left renal ischemia for 45 min followed by 24 h reperfusion	Antioxidant, anti-inflammatory		↓SC, urea, FENa+ ↑Urinary creatinine and urea ↑Urinary K+ excretion ↓Renal histopathological score	[135]
Ginkgo biloba EGb761 extract	Ginkgo biloba		Unilateral ischemia in left kidney for 60 minutes followed by 60 minutes of reperfusion	Antioxidant		↓MDA ↓Necrosis and cast formation ↑SOD, CAT	[136]
Hydroalcoholic extract	Rosa canina (fruits)		Bilateral ischemia for 45 min followed by 24 h reperfusion	Antioxidant, anti-inflammatory		↓SCr, BUN ↓Renal tissue histopathological score	[137]
	Crocus sativus		Bilateral ischemia for 30 min followed by 24 h reperfusion	Antioxidant and anti-inflammatory		↓SCr, BUN, MDA ↓Lymphocytes infiltration ↓TNF-α, ICAM-1 mRNA expression ↑FRAP	[138]
	Juglans mollis (bark)		Bilateral renal ischemia for 45 min followed by 15-hour reperfusion	Antioxidant and anti-inflammatory.		↓SCr, BUN, MDA ↑SOD ↓TNF-α, IL-1β, IL-6	[109]
Lavender oil	Lavandula angustifolia		Right nephrectomy followed by renal ischemia for 45 min followed by reperfusion for 24 hours	Attenuating oxidative stress and inflammation	Intraperitoneal posttreatment	↓SCr, BUN, MDA ↓TNFα, IL1β, IL10 ↓Apoptotic cells ↓Total histopathological score ↑SOD, GPx, catalase	[100]
Liposomes containing curcumin	Curcuma longa	Male C57BL/6 mice	Bilateral ischemia for 30 min followed by 24 h reperfusion	Targeted cellular delivery to renal tubular epithelial cells and antigen presenting cells conferring protection from IR injury, mediated by NF-kB	Intravenous pretreatment	Suppress NF-кB activity ↓SC, urea, ↓Renal histopathological score ↓TNF-α, CCL5, CCL2, CXCL2 ↓iNOS ↑SOD	[139]
Luteolin	Carrots, peppers, celery, olive oil, peppermint, thyme, rosemary, and oregano	Male Swiss albino mice	Bilateral ischemia	Antioxidant and anti-inflammatory	Pretreatment	↓SCr, BUN, MDA ↑SOD, CAT, GSH ↓TNF-α, IL-1β, IL-6 ↓Bax and caspase-3 expression ↑Bcl-2 expression	[106]
Lycopene	Tomato, apricots, papaya, pink grapefruit, guava, and watermelon		Bilateral renal ischemia for 30 min followed by reperfusion for 2 hours	Antioxidant and anti-inflammatory	Intraperitoneal pretreatment	↓ Scr, blood urea, plasma NGAL ↓Tissue Bax concentration ↓F21sop, ↓Notch2/HeS1 ↓Renal TLR 2, renal IL-6	[140]
Mangiferin	Mangifera indica also present in 16 other plant families including Anacardiacae, Gentianaceae, and Iridaceae	Male C57/BL6-mice	Left nephrectomy and right kidney ischemia for 30 min followed by 24 h reperfusion	Anti-inflammation and inducing adenosine production	Oral route pretreatment	↓SCr, BUN, ↓Plasma potassium (K+) ↓ Caspase-3 mRNA expression ↓TNF-α, IL-1β ↓NO, MPO ↑Adenosine and CD73 expression	[141]
Methanolic extract	Aruncus dioicus (whole plant)	Male Sprague Dawley rat	Right nephrectomy with left renal ischemia for 40 min followed by 24 h reperfusion	Antioxidant, antiapoptotic	Intraperitoneal route pretreatment	↓SC ↓Renal tissue histopathological score ↓Bcl-2/Bax ratio	[142]
	Cassia mimosoides var. Nomame		Right nephrectomy with left renal ischemia for 40 min followed by 24 h reperfusion	Antioxidant		↓SC ↓Caspase-3 ↓Bcl-2/Bax ratio	[143]
	Stevia rebaudiana		Left renal ischemia for 45 min with right renal nephrectomy	Antioxidant and anti-inflammatory	Oral pretreatment	↓SCr, FENa+, Creatinine clearance ↓MDA ↑GSH, Catalase	[144]
	Benincasa cerifera (fruits)	Female Wistar albino rat	Bilateral ischemia for 60 min followed by 6 h reperfusion	Free radical scavenging activity		↓SCr, BUN, uric acid, MDA ↑SOD, catalase, GSH	[145]
Nigella sativa oil	Nigella sativa (seeds)	Male Wistar albino rat	Bilateral ischemia for 60 min followed by 24 h reperfusion	Antioxidant, free radical scavenging.		↓SCr, BUN, cystatin c. ↓MDA, NO ↓Renal histopathological score ↓Total oxidant status ↑SOD, GPx (serum and renal) ↑Catalase (renal) ↑Total antioxidant capacity	[146]
Oleanolic acid	Olea europaea, Viscum album, Aralia chinensis, >120 other plant species		Bilateral renal ischemia for 45 min followed by 6 h reperfusion	Antioxidant, anti-inflammatory reductions in Nrf-2	Intraperitoneal route pretreatment	↓SCr, BUN, renal KIM-1 ↓LDH, MDA, caspase-3 expression ↓IFN-γ, IL-6, MPO ↑SOD, GST, GPx and CAT ↑IL-10 ↑Nrf-2	[85]
Osajin	Maclura pomifera		Unilateral ischemia in left renal artery for 60 min followed by 10 min reperfusion	Antioxidant	Oral route pretreatment	↑SOD, GSH-Px (serum) ↑Total antioxidant capacity ↓Renal histopathological score effectively at a dose of 10 mg	[147]
Osthole	Cnidium monnieri, Angelica pubescens, Peucedanum ostruthium		Right nephrectomy and unilateral ischemia in left kidney for 45 min followed by 1, 6, and 24 h reperfusion	Antioxidant, antiapoptotic		↓SCr, BUN ↓Caspase-3 ↑SOD, CAT ↑Bcl-2/Bax ratio	[148]
Picroliv	Picrorhiza kurrooa (roots and rhizome)	Male Sprague Dawley rat	Unilateral ischemia in left renal artery for 60 min followed by 5, 60, 120, and 240 min reperfusion	Antioxidant, antiapoptotic		↓MDA (maximal at 120 min) ↑GSH (maximal at 240 min) ↑GPx, SOD ↓NO ↓Renal ICAM-1 ↓Apoptosis	[149]
Piperine	Piper nigrum (seeds)	Male Wistar albino rat	Bilateral renal ischemia for 30 min followed by reperfusion for 24 hours	Attenuating oxidative stress and inflammation		↓SCr, BUN, MDA ↓TNF-a and ICAM-1 mRNA expression ↓Total histopathological score ↑Total FRAP level	[104]
Polysaccharide extract	Dipsacus asperoides (roots)		Bilateral ischemia for 45 min followed by 24 h reperfusion	Antioxidant		↓SCr, BUN, LDH, MDA ↑SOD, CAT, GPx	[150]
Polydatin	Polygonum cuspidatum (roots)	Male BALB/c mice primary renal tubular epithelial cells (RTECs)	Unilateral ischemia in left kidney for 30 min followed by reperfusion	Antioxidative stress and anti-inflammation by activating the sonic Hedgehog (SHH) signaling pathway	Intraperitoneal route pre and posttreatment	↓Caspase-3 expression ↑Shh mRNA expression (in vivo and in vitro) ↑SOD, GST, GPx, and CAT (in vivo)	[107]
Polyphenols	Camellia sinensis	White male rabbit	Bilateral ischemia for 30, 60, 90, and 120 min, followed by 24 h reperfusion	Antioxidant, antinecrotic	Intravenous route pretreatment	↓SCr, BUN ↓Renal histopathological score ↓Immune peroxidase labeling of CD8+T cells in kidney tissues All the results were found significant at 90 min of ischemia	[151]
Polysaccharide peptide	Ganoderma lucidum (fruits)	Male C57BL/6J mice NRK-52E cells	Left nephrectomy and right kidney ischemia for 35 min followed by 24 h reperfusion	Counteracting oxidative stress	Intraperitoneal route pretreatment	↓SCr, BUN ↓MPO, MDA ↓Bax/Bcl-2 ratio, ↑SOD, CAT, GSH and GPx ↑Cell viability	[152]
Polysaccharides	Lycium barbarum	Wistar albino rat	Bilateral renal ischemia for 45 min followed by 24 h reperfusion	Antioxidant and anti-inflammatory inhibiting apoptosis	Oral route pretreatment	↓SCr, Serum urea, MDA ↑SOD, ↓Serum IL-1β, TNF-α Enhanced renal expression of Bcl-2 mRNA	[28]
Proanthocyanidin	Grape seed	Male Sprague Dawley rat	Bilateral ischemia for 60 min followed by 6 h reperfusion	Decreasing oxidative and nitrosative stress		↓SCr, BUN, AST ↓MDA, NOx ↓Renal histopathological score ↑SOD, GPx	[153]
Pycnogenol	Pinus maritima (fresh bark)	Male Wistar albino rat	Right nephrectomy with left renal ischemia for 45 min followed by 3 h reperfusion	Antioxidant, anti-inflammatory; inhibit neutrophil infiltration	Intraperitoneal route pretreatment	↓SCr, BUN, MDA ↓TNF-a, IL-1β, and IL-6 ↓MPO ↓Renal histopathological score ↑GSH, Na+K+ ATPase	[154]
Quercetin	Apples, berries, Brassica vegetables, capers, grapes, onions, shallots, tea, tomatoes seeds, nuts, flowers, barks, and leaves	Male Swiss albino mice	Bilateral renal ischemia for 30 min followed by reperfusion for 24 hours	Attenuating oxidative stress and inflammation		↓Blood urea, SCr, plasma NGAL ↑BCl-2 level ↓Tissue Bax concentration ↓F2-isoprostane ↓Renal notch-1 jagged-1 level	[155]
Resveratrol	Grapes, wine, peanuts, soy	Male Wistar albino rat	Bilateral ischemia for 40 min followed by 24 h reperfusion	Antioxidant, free radical scavenging	Intravenous route pretreatment	↓Mortality rate ↓SCr ↓TBARS ↓Renal histopathological score ↑NO	[156, 157]
Rhizome extract	Coptidis japonica (rhizome)		Bilateral ischemia for 60 min followed by 6 and 24 h reperfusion	Antioxidant	Oral route pretreatment	↓SCr, BUN, MDA ↑SOD, catalase ↑GSH (renal) ↓DNA fragmentation rate	[17]
Rosmarinic acid	Rosmarinus officinalis, Melissa officinalis	Male Sprague Dawley rat	Right nephrectomy and ischemia in the left kidney for 60 min followed by 60 min reperfusion	By decreasing oxidative stress	Intraperitoneal route pretreatment	↓MDA, MPO ↑SOD, GPx	[158, 159]
Rutin	Buckwheat and many vegetables, fruits, beverages such as tea and wine	Male Wistar albino rat	Right nephrectomy with left renal ischemia for 45 min followed by 3 h reperfusion	Decreasing oxidative stress, anti-inflammatory		↓SCr, BUN, LDH, MDA ↓Renal histopathological score ↑GSH, MnSOD	[160]
Sesamin	Sesamum indicum (seed and oil)	Male C57/BL6 mice	Left renal nephrectomy and right kidney ischemia for 30 min followed by 24 h reperfusion	Inhibiting tubular cell death and inflammatory response, upregulating CD39-adenosine-A2AR signals	Oral Pre-treatment	↓SCr, BUN, MDA ↓Caspase-3 expression ↓Infiltration of Ly6G+ neutrophils ↓MPO activity ↓TNF-α, IL-1β ↑Adenosine level	[161]
Silymarin	Silybum marianum	Male Sprague Dawley rat	Right nephrectomy with left renal ischemia for 45 min followed by 6 h reperfusion	Anti-inflammatory, antinecrosis, free radical scavenging		↓Tubular dilatation ↓Tubular vacuolization ↓Inflammation ↓Tubular and glomerular necrosis	[162, 163]
Total flavonoids	Rosa laevigata	NRK-52E cells male Sprague Dawley rat	Bilateral renal ischemia for 45 min followed by reperfusion for 24 h	Attenuating oxidative stress and inflammation		↓SCr, BUN, MDA, ↓Levels of Keap 1 and NF-KBP65 ↓IL-1β, IL-6, TNF-α ↑Sirt 1, Nrf 2, and HO 1 ↑GSH, GPx, SOD	[108]
Ursolic acid	Crataegus sp., Arctostaphylos uva-ursi, Chinese elder herb, Actinidia deliciosa, Prunella vulgaris	Male Sprague Dawley rat	Right renal nephrectomy and left kidney ischemia for 45–90 minutes	Decrease in oxidative stress. Suppressing STAT3, NF-κB and caspase-3 activities.	Posttreatment	↓SCr, Angiotensin II ↓STAT3 protein phosphorylation ↓NF-κB expression Inhibit caspase-3 activity	[164]