Table 2.

Protective effect of mangiferin against kidney disorders based on the reported in vitro and in vivo studies.

Study models	Cell lines/ animals, sex	Mangiferin concentration/ dose, route	Duration	Outcomes	Mode of action	References
Cadmium-induced human renal endothelial damage	HRGE cells	75 µM	24 h	Cell viability ↑; ROS ↓; LPO ↓; SOD activity ↑, GPx activity ↑, DNA damage ↓; alteration of Bax and Bcl-2 inhibited; NF-κB ↓; IL-6 ↓, IL-8 ↓	Antioxidant; anti-inflammatory; anti-apoptosis	Rajendran et al. (2016)
Cisplatin-induced AKI	NKE cells	2, 5, 10, 15, 20, 25, 30, 40, 50 µM	24 h	ROS ↓; mitochondrial activity restored; caspase-3 expression ↓	Antioxidant; anti-apoptosis	Sadhukhan et al. (2018)
	Swiss albino mice, male	10, 20 a, 40 mg/kg, po	21 days	serum BUN ↓, SCr ↓; ROS ↓; CAT activity ↑, GR activity ↑, GPx activity ↑, GST activity ↑, SOD activity ↑; GSH activity ↑; MPO ↓, TNF-α ↓, IL-1β ↓, IL-6 ↓; renal histological changes ↓; mean tumour volume ↓; mean tumour mass ↓	Antioxidant; anti-inflammatory; anticancer	Sadhukhan et al. (2018)
	Albino Wistar rats, male	10, 20 a, 40 a mg/kg, ip	10 days	Serum BUN ↓, SCr ↓; MDA ↓, CAT ↑, GSH ↑, SOD ↑; TNF-α ↓, IL-6 ↓; Bax expression ↓, Bcl-2 expression ↑, caspase 3 expression ↓; NF-κBp65 ↓, ERK1/2 ↓, JNK ↓, p38 ↓	Antioxidant; anti-inflammatory; anti-apoptosis	Sahu et al. (2019)
DGal-induced nephrotoxicity	Wistar rats, male	15 mg/kg, ip	14 days	Serum BUN ↓, SCr ↓, protein carbonyl ↓, MDA ↓, ROS ↓, NO ↓; TNF-α ↓; CAT activity ↑, GR activity ↑, GPx activity ↑, GST activity ↑, SOD activity ↑; GSH activity ↑, total thiols ↑; caspase 3 and 9 expressions ↓; iNOS ↓, nuclear NF-κB ↓, IκBα ↑; histological changes ↓	Antioxidant	Ghosh et al. (2012)
Hyperuricemia (induced by hypoxathine and oteracil potassium)	ICR mice, male	50 mg/kg, po	17 days	Serum BUN ↓, SCr ↓, serum uric acid ↓; inflammatory changes ↓; NLRP3 expression ↓; fibronectin expression ↓; PKCβ expression ↓; urinary uric acid excretion ↑, AQP2 expression ↓, XO activity ↓	Antioxidant; anti-inflammatory; anti-apoptosis	Li et al. (2020)
Hyperuricemia (induced by uric acid and potassium oxonate)	Sprague- Dawley rats	1.5–24 mg/kg b, ig		Serum urate ↓, urinary urate ↑, FEUA ↑; expression of rURAT1, rGLUT9 and OAT10 ↓	Renal urate transporters downregulation	Yang et al. (2015)
Lupus nephritis	FasL-deficient B6/gld mice	20, 40 mg/kg, po	84 days	SCr ↓; urine protein ↓; α-SMA expression ↓; deposition of IgG ↓; TNF-α ↓, IL-6 ↓, IFN-γ ↓; Tregs proliferation ↑	Anti-inflammatory; immunomodulatory effects	Liang et al. (2018)
NaF-induced nephrotoxicity	NKE cells	25, 50, 75, 100 µg/ml b	24, 48, 72 h	Cell viability ↑; ROS ↓; GSH ↑, GSSH ↓	Antioxidant	Samadarsi and Dutta (2020)
Renal ischemia reperfusion injury	C57/BL6 mice, male	10, 30, 100 a mg/kg, po	7 days	Serum BUN ↓, SCr ↓; caspase-3 expression ↓; TNF-α ↓, IL-1β ↓; NO ↓; adenosine production ↑; CD-73 expression ↓	Anti-inflammatory; anti-apoptosis	Wang et al. (2015)
Sepsis-induced AKI/LPS-induced AKI	C57BL/6 mice, male	20, 50, 100 mg/kg b, po	7 days	Serum BUN ↓, SCr ↓; occludin expression restored; MMP-9 expression ↓; ROS ↓, MDA ↓; NF-κB expression ↓, HMGB1 expression ↓; kidney pathological damage ↓	Antioxidant; anti-inflammatory	Zhang et al. (2020)
	RPTC cells	10, 50, 100µm	1 h	Increase of annexin V-positive cells inhibited; caspase 3 and 9 expressions ↓; NLRP3 activity inhibited, Nrf2 activity restored	Anti-apoptosis	He et al. (2014)
	C57BL/6 mice, male	15 mg/kg, ig		Serum BUN ↓, SCr ↓, IL-1β ↓, IL-18 ↓; Nrf2 activity ↑, NLRP3 protein ↓	Antioxidant; anti-inflammatory	He et al. (2014)
STZ-induced diabetic neuropathy	Sprague- Dawley rats, male	12.5, 25, 50 mg/kg b, po	84 days	Urine protein ↓, urea nitrogen ↓, SCr ↓; nephrin expression ↑; p62 expression ↓; LC3-II/LC3-I ratio ↑; p-ULK1 ↑, AMPK and mTOR phosphorylation ↑; renal lesions improved	Autophagy	Wang et al. (2018)
	MES cells	10 µM	48 h	ROS ↓	Antioxidant	Xu et al. (2017)
	ICR mice, male	50 mg/kg, po	112 days	Serum BUN ↓, SCr ↓, urine protein ↓; Nox4 expression ↓, caspase-3 expression ↓; histological alteration ↓	Antioxidant; anti-apoptosis	Xu et al. (2017)
	Wistar rats, male	40 mg/kg, po	40 days	Serum BUN ↓, SCr ↓, serum uric acid ↓, urinary albumin ↓; plasma glucose ↓; renal injury ↓; LPO ↓, protein carbonyl ↓, GSH ↑; ROS ↓; CAT activity ↑, GR activity ↑, GPx activity ↑, SOD activity ↑; AGE formation suppressed, hydroxyproline ↓; PKCα, PKCβ and PKCɛ expression ↓; p38, JNK and ERK1/2 MAPKs activation inhibited; NF-κB ↓, IKKα ↓, IκBα ↑; TGF-1β ↓; caspase 8 and t-Bid expression ↓; alteration of Bax and Bcl-2 inhibited	Antioxidant; anti-apoptosis	Pal et al. (2014)
	Sprague- Dawley rats, male	15, 30, 60 mg/kg b, po	63 days	Urine protein ↓, serum BUN ↓, GSH ↑, MDA ↓; Glo-1 mRNA ↑, Glo-1 activity ↑; mesangial matrix expansion ↓; AGEs ↓	Antioxidant; up-regulation of Glo-1	Liu et al. (2013)
	Wistar rats, male	40 mg/kg, po	30 days	Blood glucose ↓, plasma insulin ↓; activities of HK, FBP, G6P, G6PD, LDH and PK restored	Anti-hyperglycaemic; carbohydrate metabolic enzyme activities mediation	Sellamuthu et al. (2012)
STZ-induced diabetic renal fibrosis	C57BL/6 mice, male	15, 30, 60 mg/kg b, po	28 days	Serum BUN ↓, SCr ↓, urine protein ↓; TG ↓, TC ↓; TNF-α ↓, IL-1β ↓, IL-6 ↓; ROS ↓; CAT activity ↑, GPx activity ↑, SOD activity ↑; MDA ↓; FN ↓, Col I ↓, α-SMA ↓; TGF-1β ↓	Antioxidant; anti-inflammatory	Song et al. (2020)
	Sprague- Dawley rats, male	15, 30, 60 mg/kg, po	63 days	Col IV ↓, α-SMA ↓; OPN ↓; IL-1β ↓	Anti-inflammatory	Zhu et al. (2015)
tBHP-induced renal injury	NKE cells	10–200 µM	24 h	ROS ↓; GSH activity ↑; Bax/Bcl-2 ratio ↓; caspase 8 and t-Bid expression ↓; Nrf2 ↓; morphological abnormalities ↓	Antioxidant; anti-apoptosis	Saha et al. (2016b)
	Swiss albino mice, male	75 mg/kg, po	14 days	Urine protein ↓; Serum BUN ↓, SCr ↓, urea ↓, uric acid ↓; urinary albumin ↓; ROS ↓; CAT activity ↑, GR activity ↑, GPx activity ↑, GST activity ↑, SOD activity ↑; GSH activity ↑; iNOS ↓, NO ↓; TNF-α ↓, IL-1β ↓, IL-6 ↓, MCP-1 ↓, ICAM-1 ↓, VCAM-1 ↓; morphological abnormalities ↓	Antioxidant; anti-inflammatory; anti-apoptosis	Saha et al. (2019)
Combination therapy of mangiferin and metformin
STZ-induced diabetic neuropathy	Sprague- Dawley rats, male	40 mg/kg, po	28 days	Glucose ↓; BUN ↓, creatinine ↓, albumin ↓; LPO ↓; CAT ↑, GPx ↑, GST ↑, SOD ↑; GSH ↑; expression of NF-κB, PKC, TGF-1β and VEGF ↓	Antioxidant	Sekar et al. (2020)

Abbreviations: AGEs, Advanced glycation end products; AKI, Acute renal injury; AMPK, AMP-activated protein kinase; AQP2, Aquaporin 2; Bax, Bcl-2-associated X protein; Bcl-2, B-cell lymphoma 2; BUN, Blood urea nitrogen; CAT, Catalase; Col I, type-I collagen; Col IV, type-IV collagen; DGal, D(+) galactosamine; ERK1/2, Extracellular signal-regulated kinases 1/2; FBP, Fructose-1,6-bisphosphatase; FEUA, Fractional excretion of uric acid; FN, Fibronectin; G6P, Glucose-6-phosphatase; G6PD, Glucose-6-phosphatase dehydrogenase; Glo-1, glyoxalase; GPx, Glutathione peroxidase; GR, Glutathione reductase; GSH, Reduced glutathione; GSSH, Oxidized glutathione; GST, Glutathione s-transferase; HK, Hexokinase; HMGB1, High mobility group box protein 1; HRGE, Human renal glomerulus endothelial cells; ICAM-1, Intercellular Adhesion Molecule 1; IFN-γ, Interferon γ; ig, Intragastric gavage; IgG, Immunoglobulin G; IL-1β, Interleukin-1β; IL-6, Interleukin-6; IL-8, Interleukin-8; IL-18, Interleukin-18; iNOS, inducible nitric oxide synthase; ip, Intraperitoneal injection; IκBα, Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; JNK, c-Jun N-terminal kinase; LC3-I, cytosolic form of LC3; LC3-II, LC3-phosphatidylethanolamine conjugate; LDH, Lactate dehydrogenase; LPS, Lipopolysaccharide; MAPKs, mitogen-activated protein kinases; MCP-1, Monocyte Chemoattractant Protein-1; MDA, Malondialdehyde; MES, Mouse mesangial; MMP-9, Matrix metallopeptidase 9; MPO, Myeloperoxidase; mTOR, mammalian target of rapamycin; OAT10, renal organic anion transporter 10; OPN, Osteopontin; NF-κB, Nuclear factor kappa light chain enhancer of activated B cells; NKE, Normal kidney epithelial; NLRP3, Nod-like receptor protein 3; NO, Nitric oxide; Nox4, NADPH oxidase 4; Nrf2, Nuclear factor erythroid 2-related factor 2; PK, Pyruvate kinase; PKC, Protein kinase C; po, per os, oral administration; p-ULK1, Phosphorylated Unc51-like kinase 1; rGLUT9, renal glucose transporter 9; ROS, Reactive oxygen species; RPTC, Rat kidney proximal tubular cell; rURAT1, renal urate-anion transporter 1; SCr, Serum creatinine; SOD, Superoxide dismutase; STZ, Streptozotocin; tBHP, tert-Butylhydroperoxide; t-Bid, truncated Bid; TC, Total cholesterol; TG, Triglyceride; TGF-1β, Transforming growth factor beta 1; TNF-α, T necrosis factor α; Tregs, Regulatory T cells; VCAM-1, Vascular cell adhesion molecule 1; VEGF, Vascular endothelial growth factor; α-SMA, Smooth muscle alpha-actin; XO, Xanthine oxidase

^aMost effective concentration/dose. ^b Concentration/dose dependent