Abstract
Chronic kidney disease is a syndrome defined as the continuous change of renal structure, considered as one of the top 10 causes of death worldwide. In the past few decades, dietary flavonoids and their derivatives have been proved as potential drugs to control chronic kidney disease. There also seems to be a relationship between the intake of dietary flavonoids and nephropathy incidence. This study reviews the metabolism and bioavailability of plant flavonoids with different structures and their multifunctional role in inhibiting chronic kidney disease. The alleviating effect of plant flavonoids in chronic kidney disease is attributed to several mechanisms, including reduction of oxidative stress, immune modulation anti-inflammation, renal fibrosis inhibition, anti-apoptosis, and regulating gut flora. It also discussed how plant flavonoids regulate the intestinal flora of chronic kidney disease patients and further improve renal health through the gut-kidney axis. In addition, the products and development prospect of plant flavonoids are also introduced.
Graphical abstract
The main sources of flavonoids and their related mechanisms in the treatment of chronic kidney disease
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- AT1:
-
Angiotensin type 1 receptor
- C3G:
-
Cyanidin-3-glucoside
- cAMP:
-
Cyclic adenosine monophosphate
- CAT:
-
Catalase
- CKD:
-
Chronic kidney disease
- CRP:
-
C-reactive protein
- COMT:
-
Catechol-O-methyltransferase
- DKD:
-
Diabetic nephropathy
- EMT:
-
Epithelial mesenchymal transition
- ESRD:
-
End-stage renal disease
- ECM:
-
Extracellular matrix
- EGCG:
-
(-)-Epigallocatechin-3-gallate
- GATA-3:
-
GATA binding protein 3
- GN:
-
Glomerulonephritis
- GSH:
-
Glutathione peroxidase
- GSH-Px:
-
Glutathione peroxidase
- IgA anti-GBM:
-
IgA anti-Glomerular basement membrane
- IL-1:
-
Interleukin-1
- IL-6:
-
Interleukin-6
- IL-1β:
-
Interleukin-1β
- indS:
-
Indoxyl sulfate
- LPH:
-
Lactase phloridin hydrolase
- MDA:
-
Malondialdehyde
- MAPK:
-
Mitogen activated protein kinase
- NF-κB:
-
Nuclear factor kappa-B
- NOS:
-
Nitric oxide synthase
- Nrf2:
-
Nuclear factor erythroid 2-related factor 2
- PPAR-γ:
-
Peroxisome proliferator-activated receptor-γ
- RNS:
-
Reactive nitrogen species
- pCS:
-
P-Cresyl sulfate
- ROS:
-
Reactive oxygen species
- SCFA:
-
Short chain fatty acids
- STAT3:
-
Signal transducer and activator of transcription 3
- STAT-6:
-
Signal transducer and activator of transcription 6
- SOD:
-
Superoxide dismutase
- TGF-β1:
-
Transforming growth factor-β1
- TMAO:
-
Trimethylamine-N-oxide
- TNF-α:
-
Tumor necrosis factor-α
- UGT:
-
UDP glucuronosyltransferase
References
Alam MdA, Islam P, Subhan N, Rahman M, Khan F, Burrows GE, Nahar L, Sarker SD (2021) Potential health benefits of anthocyanins in oxidative stress related disorders. Phytochem Rev 20:705–774. https://doi.org/10.1007/s11101-021-09757-1
Ali BH, Al Za’abi M, Adham SA, Al Suleimani Y, Karaca T, Manoj P, Al Kalbani J, Yasin J, Nemmar A (2018) The effect of sildenafil on rats with adenine—Induced chronic kidney disease. Biomed Pharmacother 108:391–402. https://doi.org/10.1016/j.biopha.2018.09.061
Alidadi H, Khorsandi L, Shirani M (2018) Effects of quercetin on tubular cell apoptosis and kidney damage in rats induced by titanium dioxide nanoparticles. Malays J Med Sci 25(2):72–81. https://doi.org/10.21315/mjms2018.25.2.8
Alvarez Cilleros D, Lopez-Oliva ME, Martin MA, Ramos S (2020) (-)-Epicatechin and the colonic metabolite 2,3-dihydroxybenzoic acid protect against high glucose and lipopolysaccharide-induced inflammation in renal proximal tubular cells through NOX-4/p38 signalling. Food Funct 11(10):8811–8824. https://doi.org/10.1039/d0fo01805h
Alzaabi MM, Alzaabi MM, El-Keblawy AA, Hamdy R, Ashmawy NS, Hamoda AM, Alkhayat F, Khademi NN, Al Joud SMA, Soliman SSM (2022) Flavonoids are promising safe therapy against COVID-19. Phytochem Rev 21:291–312. https://doi.org/10.1007/s11101-021-09759-z
Amelia VD, Aversano R, Chiaiese P, Carputo D (2018) The antioxidant properties of plant flavonoids: their exploitation by molecular plant breeding. Phytochem Rev 17:611–625. https://doi.org/10.1007/s11101-018-9568
American Society of Nephrology (ASN) (2018) European Renal Association – European Dialysis and Transplant Association (ERA-EDTA), International Society of Nephrology (ISN) (2018) The hidden epidemic: Worldwide, over 850 million people suffer from kidney diseases. https://www.asn-online.org/news/2018/0626-Joint_Hidden_Epidem.pdf.
Anothaisintawee T, Rattanasiri S, Ingsathit A, Attia J, Thakkinstian A (2009) Prevalence of chronic kidney disease: a systematic review and meta-analysis. Clin Nephrol 71(3):244–254. https://doi.org/10.5414/cnp71244
Athmouni K, Belhaj D, El Feki A, Ayadi H (2018) Optimization, antioxidant potential, modulatory effect and anti-apoptotic action in of Euphorbia bivonae polysaccharides on hydrogen peroxide-induced toxicity in human embryonic kidney cells HEK293. Int J Biol Macromol 116:482–491. https://doi.org/10.1016/j.ijbiomac.2018.04.172
Aura AM, Martin-Lopez P, O’Leary KA, Williamson G, Oksman-Caldentey KM, Poutanen K, Santos-Buelga C (2005) In vitro metabolism of anthocyanins by human gut microflora. Eur J Nutr 44(3):133–142. https://doi.org/10.1007/s00394-004-0502-2
Bahadoran Z, Mirmiran P, Momenan AA, Azizi F (2017) Allium vegetable intakes and the incidence of cardiovascular disease, hypertension, chronic kidney disease, and type 2 diabetes in adults: a longitudinal follow-up study. J Hypertens 35(9):1909–1916. https://doi.org/10.1097/hjh.0000000000001356
Baky MH, Elshahed M, Wessjohann L, Farag MA (2021) Interactions between dietary flavonoids and the gut microbiome: a comprehensive review. Br J Nutr 9(13):1–15. https://doi.org/10.1017/S0007114521003627
Barreca D, Trombetta D, Smeriglio A, Mandalari G, Romeo O, Felice MR, Nabavi SM (2021) Food flavonols: Nutraceuticals with complex health benefits and functionalities. Trends Food Sci Technol 117:194–204. https://doi.org/10.1016/j.tifs.2021.03.030
Bosetti C, Rossi M, McLaughlin JK, Negri E, Talamini R, Lagiou P, Montella M, Ramazzotti V, Franceschi S, LaVecchia C (2007) Flavonoids and the risk of renal cell carcinoma. Cancer Epidemiol Biomarkers Prev 16(1):98–101. https://doi.org/10.1158/1055-9965.EPI-06-0769
Burlaka I, Nilsson LM, Scott L, Holtback U, Eklof AC, Fogo AB, Brismar H, Aperia A (2016) Prevention of apoptosis averts glomerular tubular disconnection and podocyte loss in proteinuric kidney disease. Kidney Int 90(1):135–148. https://doi.org/10.1016/j.kint.2016.03.026
Cai HD, Su SL, Qian DW, Guo S, Tao WW, Cong XD, Tang R, Duan JA (2017a) Renal protective effect and action mechanism of Huangkui capsule and its main five flavonoids. J Ethnopharmacol 206:152–159. https://doi.org/10.1016/j.jep.2017.02.046
Cai Y, Ma W, Xiao Y, Wu B, Li X, Liu F, Qiu J, Zhang G (2017b) High doses of baicalin induces kidney injury and fibrosis through regulating TGF-beta/Smad signaling pathway. Toxicol Appl Pharmacol 333:1–9. https://doi.org/10.1016/j.taap.2017.08.003
Caro-Ordieres T, Marin-Royo G, Opazo-Rios L, Jimenez-Castilla L, Moreno JA, Gomez-Guerrero C, Egido J (2020) The coming age of flavonoids in the treatment of diabetic complications. J Clin Med 9(2):346. https://doi.org/10.3390/jcm9020346
Chen X, Wei W, Li Y, Huang J, Ci X (2019a) Hesperetin relieves cisplatin-induced acute kidney injury by mitigating oxidative stress, inflammation and apoptosis. Chem Biol Interact 308:269–278. https://doi.org/10.1016/j.cbi.2019.05.040
Chen YJ, Kong L, Tang ZZ, Zhang YM, Liu Y, Wang TY, Liu YW (2019b) Hesperetin ameliorates diabetic nephropathy in rats by activating Nrf2/ARE/glyoxalase 1 pathway. Biomed Pharmacother 111:1166–1175. https://doi.org/10.1016/j.biopha.2019.01.030
Chen L, Yao M, Fan X, Lin X, Arroo R, Silva A, Sungthong B, Dragan S, Paoli P, Wang S, Teng H, Xiao J (2020) Dihydromyricetin Attenuates Streptozotocin-induced Liver Injury and Inflammation in Rats via Regulation of NF-κB and AMPK Signaling Pathway. Food 1(2):188–195. https://doi.org/10.2991/efood.k.200207.00
Cheong HC, Lee CYQ, Cheok YY, Shankar EM, Sabet NS, Tan GMY, Movahed E, Yeow TC, Sulaiman S, Wong WF (2019) CPAF, HSP60 and MOMP antigens elicit pro-inflammatory cytokines production in the peripheral blood mononuclear cells from genital Chlamydia trachomatis-infected patients. Immunobiology 224(1):34–41. https://doi.org/10.1016/j.imbio.2018.10.010
Choi JS, Chung HY, Kang SS, Jung MJ, Kim JW, No JK, Jung HA (2002) The structure-activity relationship of flavonoids as scavengers of peroxynitrite. Phytother Res 16(3):232–235. https://doi.org/10.1002/ptr.828
Clemente-Postigo M, Oliva-Olivera W, Coin-Araguez L, Ramos-Molina B, Giraldez-Perez RM, Lhamyani S, Alcaide-Torres J, Perez-Martinez P, El Bekay R, Cardona F, Tinahones FJ (2019) Metabolic endotoxemia promotes adipose dysfunction and inflammation in human obesity. Am J Physiol Endocrinol Metab 316(2):E319–E332. https://doi.org/10.1152/ajpendo.00277.2018
Cremonini E, Daveri E, Mastaloudis A, Adamo AM, Mills D, Kalanetra K, Hester SN, Wood SM, Fraga CG, Oteiza PI (2019) Anthocyanins protect the gastrointestinal tract from high fat diet-induced alterations in redox signaling, barrier integrity and dysbiosis. Redox Biol 26:101269. https://doi.org/10.1016/j.redox.2019.101269
Daenen K, Andries A, Mekahli D, Van Schepdael A, Jouret F, Bammens B (2019) Oxidative stress in chronic kidney disease. Pediatr Nephrol 34(6):975–991. https://doi.org/10.1007/s00467-018-4005-4
de Pascual-Teresa S, Sanchez-Ballesta MT (2007) Anthocyanins: from plant to health. Phytochem Rev 7:281–299. https://doi.org/10.1007/s11101-007-9074-0
Ding Q, Bao J, Zhao W, Hu Y, Lu J, Chen X (2015) Natural autophagy regulators in cancer therapy: a review. Phytochem Rev 14:137–154. https://doi.org/10.1007/s11101-014-9339-3
Ding Y, Li H, Li Y, Liu D, Zhang L, Wang T, Liu T, Ma L (2020) Protective effects of grape seed proanthocyanidins on the kidneys of diabetic rats through the Nrf2 signalling pathway. Evid Based Complement Alternat Med 2020:5205903. https://doi.org/10.1155/2020/5205903
Du X, Fan L (2012) Prevalence of chronic kidney disease in China. The Lancet 380(9838):815–822. https://doi.org/10.1016/s0140-6736(12)61208-2
Duda-Chodak A, Tarko T, Satora P, Sroka P (2015) Interaction of dietary compounds, especially polyphenols, with the intestinal microbiota: a review. Eur J Nutr 54(3):325–341. https://doi.org/10.1007/s00394-015-0852-y
Eknoyan G, Lameire N, Eckardt K-U, Kasiske BL, Wheeler DC, Abboud OI, Jadoul M, Adler S, Jenkins S (2013) Chapter 1: Definition, and classification of CKD. In KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl, 3:1–150.
Escobar-Cévoli R, Castro-Espín C, Béraud V, Buckland G, Zamora-Ros R (2017) An overview of global flavonoid intake and its food sources. Flavonoids—From Biosynthesis to Human Health. https://doi.org/10.5772/67655
Feng XL, Ho SC, Mo XF, Lin FY, Zhang NQ, Luo H, Zhang X, Zhang CX (2020) Association between flavonoids, flavonoid subclasses intake and breast cancer risk: a case-control study in China. Eur J Cancer Prev 29(6):493–500. https://doi.org/10.1097/CEJ.0000000000000561
Fletcher RJ (2003) Food sources of phyto-oestrogens and their precursors in Europe. British J Nutr 89(S1):S39–S43. https://doi.org/10.1079/BJN2002795
Fornasaro S, Ziberna L, Gasperotti M, Tramer F, Vrhovsek U, Mattivi F, Passamonti S (2016) Determination of cyanidin 3-glucoside in rat brain, liver and kidneys by UPLC/MS-MS and its application to a short-term pharmacokinetic study. Sci Rep 6:22815. https://doi.org/10.1038/srep22815
Greene IJD, Gradworks T (2015) Kaempferol and Esculetin as potential therapeutic agents in chronic renal allograft injury. Icahn school of medicine at mount sinai proquest dissertations publishing, 1595299.
Guo J, Du L, Shang E, Li T, Liu Y, Qian D, Tang Y, Duan J (2016) Conjugated metabolites represent the major circulating forms of Abelmoschus manihot in vivo and show an altered pharmacokinetic profile in renal pathology. Pharm Biol 54(4):595–603. https://doi.org/10.3109/13880209.2015.1068337
Guo S, Sun J, Zhuang Y (2020) Quercetin alleviates lipopolysaccharide-induced inflammatory responses by up-regulation miR-124 in human renal tubular epithelial cell line HK-2. BioFactors 46(3):402–410. https://doi.org/10.1002/biof.1596
Han C, Sun T, Liu Y, Fan G, Zhang W, Liu C (2020) Protective effect of Polygonatum sibiricum polysaccharides on gentamicin-induced acute kidney injury in rats via inhibiting p38 MAPK/ATF2 pathway. Int J Biol Macromol 151:595–601. https://doi.org/10.1016/j.ijbiomac.2020.02.049
Heerspink HJL, Parving H-H, Andress DL, Bakris G, Correa-Rotter R, Hou F-F, Kitzman DW, Kohan D, Makino H, McMurray JJV (2019) Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. The Lancet 393(10184):1937–1947. https://doi.org/10.1016/s0140-6736(19)30772-x
Higbee J, Solverson P, Zhu M, Carbonero F (2021) The emerging role of dark berry polyphenols in human health and nutrition. Food Frontiers 3:3–27. https://doi.org/10.1002/fft2.128
Hinchman CA, Ballatori N (1994) Glutathione conjugation and conversion to mercapturic acids can occur as an intrahepatic process. J Toxicol Environ Health 41(4):387–409. https://doi.org/10.1080/15287399409531852
Hossain CM (2014) Apigenin causes biochemical modulation, glut4 and cd38 alterations to improve diabetes and to protect damages of some vital organs in experimental diabetes. Am J Pharmacol Toxicol 9(1):39–52. https://doi.org/10.3844/ajptsp.2014.39.52
Huang J, Chen L, Xue B, Liu Q, Ou S, Wang Y, Peng X (2016) Different flavonoids can shape unique gut microbiota profile in vitro. J Food Sci 81(9):2773–2279. https://doi.org/10.1111/1750-3841.13411
Hung WL, Chang WS, Lu WC, Wei GJ, Wang Y, Ho CT, Hwang LS (2018) Pharmacokinetics, bioavailability, tissue distribution and excretion of tangeretin in rat. J Food Drug Anal 26(2):849–857. https://doi.org/10.1016/j.jfda.2017.08.003
Ivey KL, Lewis JR, Lim WH, Lim EM, Hodgson JM, Prince RL (2013) Associations of proanthocyanidin intake with renal function and clinical outcomes in elderly women. PLoS ONE 8(8):e71166. https://doi.org/10.1371/journal.pone.0071166
Jeon BJ, Yang HM, Lyu YS, Pae HO, Ju SM, Jeon BH (2015) Apigenin inhibits indoxyl sulfate-induced endoplasmic reticulum stress and anti-proliferative pathways, CHOP and IL-6/p21, in human renal proximal tubular cells. Eur Rev Med Pharmacol Sci 19:2303–2310
Jiang S, Xie S, Lv D, Zhang Y, Deng J, Zeng L, Chen Y (2016) A reduction in the butyrate producing species Roseburia spp. and Faecalibacterium prausnitzii is associated with chronic kidney disease progression. Antonie Van Leeuwenhoek 109(10):1389–1396. https://doi.org/10.1007/s10482-016-0737-y
Jiang Y, Liu J, Zhou Z, Liu K, Liu C (2018) Diosmetin attenuates akt signaling pathway by modulating nuclear factor kappa-light-chain-enhancer of activated B Cells (NF-κB)/Inducible Nitric Oxide Synthase (iNOS) in Streptozotocin (STZ)-induced diabetic nephropathy mice. Medical Sci Monitor 24:7007–7014. https://doi.org/10.12659/MSM.910764
Jin Y, Arroo RRJ (2021) Application of dietary supplements in the prevention of type 2 diabetes-related cardiovascular complications. Phytochem Rev 20:181–209. https://doi.org/10.1007/s11101-020-09710-8
Jing Z, Wei Y (2016) Effects of soy protein containing isoflavones in patients with chronic kidney disease: A systematic review and meta-analysis. Clin Nutr 35(1):117–124. https://doi.org/10.1016/j.clnu.2015.03.012
Jing LV, Yang GQ, Zhang JJ (2013) Effect of Qiji shenkang granule total polysaccharide extract on IL-6 and mcp-1 in glomerular mesangial cells of rats. Chin J ETMF 19(12):239–241
Kakuta Y, Okumi M, Isaka Y, Tsutahara K, Abe T, Yazawa K, Ichimaru N, Matsumura K, Hyon SH, Takahara S, Nonomura N (2011) Epigallocatechin-3-gallate protects kidneys from ischemia reperfusion injury by HO-1 upregulation and inhibition of macrophage infiltration. Transpl Int 24(5):514–522. https://doi.org/10.1111/j.1432-2277.2011.01224
Kandasamy N, Ashokkumar N (2012) Myricetin, a natural flavonoid, normalizes hyperglycemia in streptozotocin-cadmium-induced experimental diabetic nephrotoxic rats. Biomed Prev Nutr 2(4):246–251. https://doi.org/10.1016/j.bionut.2012.04.003
Kanlaya R, Thongboonkerd V (2019) Protective effects of epigallocatechin-3-gallate from green tea in various kidney diseases. Adv Nutr 10(1):112–121. https://doi.org/10.1093/advances/nmy077
Kato M, Yuan H, Xu ZG, Lanting L, Li SL, Wang M, Natarajan R (2006) Role of the Akt/FoxO3a pathway in TGF-β1–mediated mesangial cell dysfunction: a novel mechanism related to diabetic kidney disease. J Am Soc Nephrol 17(12):3325–3335. https://doi.org/10.1681/ASN.2006070754
Katsumata M, Hirawa N, Sumida K, Kagimoto M, Ehara Y, Okuyama Y, Fujita M, Fujiwara A, Kobayashi M, Kobayashi Y (2017) Effects of tolvaptan in patients with chronic kidney disease and chronic heart failure. Clin Exp Nephrol 21(5):858–865. https://doi.org/10.1681/ASN.2006070754
Kawabata K, Yoshioka Y, Terao J (2019) Role of intestinal microbiota in the bioavailability and physiological functions of dietary polyphenols. Molecules 24(2):370. https://doi.org/10.3390/molecules24020370
Khan H, Ullah H, Tundis R, Belwal T, Devkota HP, Daglia M, Cetin Z, Saygili EI, Campos MG, Capanoglu E, Du M, Dar P, Xiao J (2020) Dietary flavonoids in the management of huntington’s disease: mechanism and clinical perspective. Food 1(1):38–52
Khan M, Liu H, Wang J, Sun B (2020b) Inhibitory effect of phenolic compounds and plant extracts on the formation of advance glycation end products: A comprehensive review. Food Res Int 130:108933. https://doi.org/10.1016/j.foodres.2019.108933
Kikuchi M, Ueno M, Itoh Y, Suda W, Hattori M (2017) Uremic toxin-producing gut microbiota in rats with chronic kidney disease. Nephron 135(1):51–60. https://doi.org/10.1159/000450619
Kim MJ, Lim Y (2013) Protective effect of short-term genistein supplementation on the early stage in diabetes-induced renal damage. Mediators Inflamm 2013:510212. https://doi.org/10.1155/2013/510212
Kirakosyan A, Seymour EM, Wolforth J, McNish R, Kaufman PB, Bolling SF (2015) Tissue bioavailability of anthocyanins from whole tart cherry in healthy rats. Food Chem 171:26–31. https://doi.org/10.1016/j.foodchem.2014.08.114
Kumar A, Aswal S, Semwal RB, Chauhan A, Joshi SK, Semwal DK (2019) Role of plant-derived alkaloids against diabetes and diabetes-related complications: a mechanism-based approach. Phytochem Rev 18:1277–1298. https://doi.org/10.1007/s11101-019-09648-6
Lee J, Park S-H (2018) Daidzein Has Anti-Oxidant Activity in Normal Human Kidney Tubular HK-2 Cells via FOXO3/SOD2 Pathway. J Food Nutr Res 6(9):557–560. https://doi.org/10.12691/jfnr-6-9-3
Lee EK, Kim JM, Choi J, Jung KJ, Kim DH, Chung SW, Chung HY (2011) Modulation of NF-κB and FOXOs by baicalein attenuates the radiation-induced inflammatory process in mouse kidney. Free Radic Res 45(5):507–517. https://doi.org/10.3109/10715762.2011.555479
Li BY, Cheng M, Gao HQ, Ma YB, Xu L, Li XH, Li XL, You BA (2008) Back-regulation of six oxidative stress proteins with grape seed proanthocyanidin extracts in rat diabetic nephropathy. J Cell Biochem 104(2):668–679. https://doi.org/10.1002/jcb.21658
Li Y, Yu Q, Zhao W, Zhang J, Liu W, Huang M, Zeng X (2017) Oligomeric proanthocyanidins attenuate airway inflammation in asthma by inhibiting dendritic cells maturation. Mol Immunol 91:209–217. https://doi.org/10.1016/j.molimm.2017.09.012
Li Y, Chen F, Wei A, Bi F, Zhu X, Yin S, Lin W, Cao W (2019) Klotho recovery by genistein via promoter histone acetylation and DNA demethylation mitigates renal fibrosis in mice. Int J Mol Med 97(4):541–552. https://doi.org/10.1007/s00109-019-01759-z
Li Y, Chen Y, Zhou L, You S, Deng H, Chen Y, Alseekh S, Yuan Y, Fu R, Zhang Z, Su D, Fernie AR, Bouzayen M, Ma T, Liu M, Zhang Y (2020) Microtom metabolic network: rewiring tomato metabolic regulatory network throughout the growth cycle. Mol Plant 13(8):1203–1218. https://doi.org/10.1016/j.molp.2020.06.005
Li H, Feng Y, Sun W, Kong Y, Jia L (2021) Antioxidation, anti-inflammation and anti-fibrosis effect of phosphorylated polysaccharides from Pleurotus djamor mycelia on adenine-induced chronic renal failure mice. Int J Biol Macromol 170:652–663. https://doi.org/10.1016/j.ijbiomac.2020.12.159
Lim H, Heo MY, Kim HP (2019) Flavonoids: broad spectrum agents on chronic inflammation. Biomol Ther (seoul) 27(3):241–253. https://doi.org/10.4062/biomolther.2019.034
Liu C, Weir D, Busse P, Yang N, Zhou Z, Emala C, Li XM (2015) The flavonoid 7,4’-dihydroxyflavone inhibits MUC5AC gene expression, production, and secretion via regulation of NF-kappaB, STAT6, and HDAC2. Phytother Res 29(6):925–932. https://doi.org/10.1002/ptr.5334
Liu X, Sun N, Mo N, Lu S, Song E, Ren C, Li Z (2019a) Quercetin inhibits kidney fibrosis and the epithelial to mesenchymal transition of the renal tubular system involving suppression of the Sonic Hedgehog signaling pathway. Food Funct 10(6):3782–3797. https://doi.org/10.1039/c9fo00373h
Liu ZZ, Weng HB, Zhang LJ, Pan LY, Sun W, Chen HX, Chen MY, Zeng T, Zhang YY, Chen DF, Li H (2019b) Bupleurum polysaccharides ameliorated renal injury in diabetic mice associated with suppression of HMGB1-TLR4 signaling. Chin J Nat Medicines 17(9):641–649. https://doi.org/10.1016/s1875-5364(19)30078-0
Liu T, Yang Q, Zhang X, Qin R, Shan W, Zhang H, Chen X (2020) Quercetin alleviates kidney fibrosis by reducing renal tubular epithelial cell senescence through the SIRT1/PINK1/mitophagy axis. Life Sci 257:118116. https://doi.org/10.1016/j.lfs.2020.118116
Lopez-Novoa JM, Martinez-Salgado C, Rodriguez-Pena AB, Lopez-Hernandez FJ (2010) Common pathophysiological mechanisms of chronic kidney disease: therapeutic perspectives. Pharmacol Ther 128(1):61–81. https://doi.org/10.1016/j.pharmthera.2010.05.006
Lu H, Wu L, Liu L, Ruan Q, Zhang X, Hong W, Wu S, Jin G, Bai Y (2018) Quercetin ameliorates kidney injury and fibrosis by modulating M1/M2 macrophage polarization. Biochem Pharmacol 154:203–212. https://doi.org/10.1016/j.bcp.2018.05.007
Manach C, Texier O, Régérat F, Agullo G, Demigné C, Rémésy C (1996) Dietary quercetin is recovered in rat plasma as conjugated derivatives of isorhamnetin and quercetin. J Nutr Biochem 7(7):375–380. https://doi.org/10.1016/S0955-2863(96)00058-7
Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L (2004) Polyphenols: food sources and bioavailability. Am J Clin Nutr 79(5):727–747. https://doi.org/10.1093/ajcn/79.5.727
Marilina A, Scott RH, Gurjeet B, Lauren H, Ben O, Sally H, Mark H, Alan DS (2019) Binding truths: Atypical anti-glomerular basement membrane disease mediated by IgA anti-glomerular basement membrane antibodies targeting the α1 chain of type IV collagen. Kidney Int Rep 4(1):163–167. https://doi.org/10.1016/j.ekir.2018.08.005
Meijers B, Farre R, Dejongh S, Vicario M, Evenepoel P (2018) Intestinal Barrier Function in Chronic Kidney Disease. Toxins (basel) 10(7):298. https://doi.org/10.3390/toxins10070298
Meng H, Fu G, Shen J, Shen K, Xu Z, Wang Y, Jin B, Pan H (2017) Ameliorative effect of daidzein on cisplatin-induced nephrotoxicity in mice via modulation of inflammation, oxidative stress, and cell death. Oxid Med Cell Longev 2017:3140680. https://doi.org/10.1155/2017/3140680
Miranda AM, Steluti J, Fisberg RM, Marchioni DM (2016) Dietary intake and food contributors of polyphenols in adults and elderly adults of Sao Paulo: a population-based study. Br J Nutr 115(6):1061–1070. https://doi.org/10.1017/S0007114515005061
Mou J, Qiu S, Chen D, Deng Y, Tekleab T (2021) Design, synthesis, and primary activity assays of baicalein derivatives as cyclin-dependent kinase 1 inhibitors. Chem Biol Drug Des 98(4):639–654. https://doi.org/10.1111/cbdd.13917
Murad HA, Habib H, Kamel Y, Alsayed S, Shakweer M, Elshal M (2016) Thearubigins protect against acetaminophen-induced hepatic and renal injury in mice: biochemical, histopathological, immunohistochemical, and flow cytometry study. Drug Chem Toxicol 39(2):190–198. https://doi.org/10.3109/01480545.2015.1070170
Oyagbemi AA, Akinrinde AS, Adebiyi OE, Jarikre TA, Omobowale TO, Ola-Davies OE, Saba AB, Emikpe BO, Adedapo AA (2020) Luteolin supplementation ameliorates cobalt-induced oxidative stress and inflammation by suppressing NF-small ka, CyrillicB/Kim-1 signaling in the heart and kidney of rats. Environ Toxicol Pharmacol 80:103488. https://doi.org/10.1016/j.etap.2020.103488
Oza MJ, Kulkarni YA (2019) Formononetin attenuates kidney damage in type 2 diabetic rats. Life Sci 219:109–121. https://doi.org/10.1016/j.lfs.2019.01.013
Panche AN, Diwan AD, Chandra SR (2016) Flavonoids: an overview. J Nutr Sci 5:e47. https://doi.org/10.1017/jns.2016.41
Pei R, Liu X, Bolling B (2020) Flavonoids and gut health. Curr Opin Biotechnol 61:153–159. https://doi.org/10.1016/j.copbio.2019.12.018
Perazella MA, Nolin TD (2020) Adverse drug effects in patients with ckd: primum non nocere. Clin J Am Soc Nephrol 15(8):1075–1077. https://doi.org/10.2215/CJN.08890620
Pereira RB, Sousa C, Costa A, Andrade PB, Valentao P (2013) Glutathione and the antioxidant potential of binary mixtures with flavonoids: synergisms and antagonisms. Molecules 18(8):8858–8872. https://doi.org/10.3390/molecules18088858
Prince PD, Fraga CG, Galleano M (2020) (-)-Epicatechin administration protects kidneys against modifications induced by short-term l-NAME treatment in rats. Food Funct 11(1):318–327. https://doi.org/10.1039/c9fo02234a
Qin Y, Zhai Q, Li Y, Cao M, Xu Y, Zhao K, Wang T (2018) Cyanidin-3-O-glucoside ameliorates diabetic nephropathy through regulation of glutathione pool. Biomed Pharmacother 103:1223–1230. https://doi.org/10.1016/j.biopha.2018.04.137
Rapa SF, Di Iorio BR, Campiglia P, Heidland A, Marzocco S (2019) Inflammation and oxidative stress in chronic kidney disease-potential therapeutic role of minerals, vitamins and plant-derived metabolites. Int J Mol Sci 21(1):263. https://doi.org/10.3390/ijms21010263
Ren Q, Guo F, Tao S, Huang R, Ma L, Fu P (2020) Flavonoid fisetin alleviates kidney inflammation and apoptosis via inhibiting Src-mediated NF-kappaB p65 and MAPK signaling pathways in septic AKI mice. Biomed Pharmacother 122:109772. https://doi.org/10.1016/j.biopha.2019.109772
Renmao T (2016) Total flavone extract of abelmoschus manihot and preparation method thereof (China Patent No. L. Jiangsu Suzhong Pharmaceutical Group Co.)
Romagnani P, Remuzzi G, Glassock R, Levin A, Jager KJ, Tonelli M, Massy Z, Wanner C, Anders HJ (2017) Chronic kidney disease. Nat Rev Dis Primers 3:17088. https://doi.org/10.1038/nrdp.2017.88
Salahshoor MR, Jalili C, Rashidi I, Roshankhah S, Jalili F (2020) Protective effect of genistein on the morphine-induced kidney disorders in male mice. Int J Gen Med 17(3):213. https://doi.org/10.29333/ejgm/7874
Sallam IE, Abdelwareth A, Attia H, Aziz RK, Homsi MN, von Bergen M, Farag MA (2021) Effect of gut microbiota biotransformation on dietary tannins and human health implications. Microorganisms 9(5):965. https://doi.org/10.3390/microorganisms9050965
Sebastian RS, Wilkinson Enns C, Goldman JD, Martin CL, Steinfeldt LC, Murayi T, Moshfegh AJ (2015) A new database facilitates characterization of flavonoid intake, sources, and positive associations with diet quality among US adults. J Nutr 145(6):1239–1248. https://doi.org/10.3945/jn.115.213025
Sharma D, Kumar Tekade R, Kalia K (2020) Kaempferol in ameliorating diabetes-induced fibrosis and renal damage: An in vitro and in vivo study in diabetic nephropathy mice model. Phytomedicine 76:153235. https://doi.org/10.1016/j.phymed.2020.153235
Slamova K, Kapesova J, Valentova K (2018) “Sweet flavonoids”: glycosidase-catalyzed modifications. Int J Mol Sci 19(7):2126. https://doi.org/10.3390/ijms19072126
Song SE, Jo HJ, Kim YW, Cho YJ, Kim JR, Park SY (2016) Delphinidin prevents high glucose-induced cell proliferation and collagen synthesis by inhibition of NOX-1 and mitochondrial superoxide in mesangial cells. J Pharmacol Sci 130(4):235–243. https://doi.org/10.1016/j.jphs.2016.03.005
Song X, Pang H, Cui W, Zhang J, Li J, Jia L (2021) Renoprotective effects of enzyme-hydrolyzed polysaccharides from Auricularia polytricha on adenine-induced chronic kidney diseases in mice. Biomed Pharmacother 135:111004. https://doi.org/10.1016/j.biopha.2020.111004
Stevens JF, Maier CS (2016) The chemistry of gut microbial metabolism of polyphenols. Phytochem Rev 15(3):425–444. https://doi.org/10.1007/s11101-016-9459-z
Sun CY, Hsu HH, Wu MS (2013) p-Cresol sulfate and indoxyl sulfate induce similar cellular inflammatory gene expressions in cultured proximal renal tubular cells. Nephrol Dial Transplant 28(1):70–78. https://doi.org/10.1093/ndt/gfs133
Sun C, Zhao C, Guven EC, Paoli P, Simal-Gandara J, Ramkumar KM, Wang S, Buleu F, Pah A, Turi V, Damian G, Dragan S, Tomas M, Khan W, Wang M, Delmas D, Portillo MP, Dar P, Chen L, Xiao J (2020) Dietary polyphenols as antidiabetic agents: Advances and opportunities. Food Frontiers 1:18–44. https://doi.org/10.1002/fft2.1
Tang Y, Li T, Peng L, Liu J, Wang Y, Piao C (2019) Dose-response regulation system for improving renal injury in diabetic nephropathy by buckwheat hull flavonoids. J Funct Foods 62:103561. https://doi.org/10.1016/j.jff.2019.103561
Tomar A, Kaushik S, Khan SI, Bisht K, Nag TC, Arya DS, Bhatia J (2019) The dietary isoflavone daidzein mitigates oxidative stress, apoptosis, and inflammation in CDDP-induced kidney injury in rats: Impact of the MAPK signaling pathway. J Biochem Mol Toxic 34(2):e22431. https://doi.org/10.1002/jbt.22431
Tominaga N, Kida K, Inomata T, Sato N, Izumi T, Akashi YJ, Shibagaki Y (2017) Effects of tolvaptan addition to furosemide in normo- and hyponatremia patients with heart failure and chronic kidney disease stages G3b–5: A subanalysis of the K-STAR study. Am J Nephrol 46(5):417–426. https://doi.org/10.1159/000481995
Tuttle KR, Brosius FC 3rd, Adler SG, Kretzler M, Mehta RL, Tumlin JA, Tanaka Y, Haneda M, Liu J, Silk ME, Cardillo TE (2018) JAK1/JAK2 inhibition by baricitinib in diabetic kidney disease: results from a Phase 2 randomized controlled clinical trial. Nephrol Dial Transplant 33(11):1950–1959. https://doi.org/10.1093/ndt/gfx377
Vanzo A, Vrhovsek U, Tramer F, Mattivi F, Passamonti S (2011) Exceptionally fast uptake and metabolism of cyanidin 3-glucoside by rat kidneys and liver. J Nat Prod 74(5):1049–1054. https://doi.org/10.1021/np100948a
Vazhappilly CG, Amararathna M, Cyril AC, Linger R, Matar R, Merheb M, Rupasinghe HV (2021) Current methodologies to refine bioavailability, delivery, and therapeutic efficacy of plant flavonoids in cancer treatment. J Nutr Biochem 94:108623. https://doi.org/10.1016/j.jnutbio.2021.108623
Walle T (2004) Absorption and metabolism of flavonoids. Free Radic Biol Med 36(7):829–837. https://doi.org/10.1016/j.freeradbiomed.2004.01.002
Wang W, Zhou PH, Xu CG, Zhou XJ, Hu W, Zhang J (2015) Baicalein attenuates renal fibrosis by inhibiting inflammation via down-regulating NF-kappaB and MAPK signal pathways. J Mol Histol 46(3):283–290. https://doi.org/10.1007/s10735-015-9621-8
Wang T, Miao M, Bai M, Li Y, Li M, Li C, Xu Y (2017) Effect of sophora japonica total flavonoids on pancreas, kidney tissue morphology of streptozotocin-induced diabetic mice model. Saudi J Biol Sci 24(3):741–747. https://doi.org/10.1016/j.sjbs.2017.01.051
Wang S, Sun Z, Yang S, Chen B, Shi J (2018) CTRP6 inhibits cell proliferation and ECM expression in rat mesangial cells cultured under TGF-beta1. Biomed Pharmacother 97:280–285. https://doi.org/10.1016/j.biopha.2017.10.091
Wang Z, Wang S, Zhao J, Yu C, Hu Y, Tu Y, Yang Z, Zheng J, Wang Y, Gao Y (2019) Naringenin ameliorates renovascular hypertensive renal damage by normalizing the balance of renin-angiotensin system components in rats. Int J Med Sci 16(5):644–653. https://doi.org/10.7150/ijms.31075
Wei X, Gao P, Pu Y, Li Q, Yang T, Zhang H, Xiong S, Cui Y, Li L, Ma X, Liu D, Zhu Z (2017) Activation of TRPV4 by dietary apigenin antagonizes renal fibrosis in deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Clin Sci (lond) 131(7):567–581. https://doi.org/10.1042/CS20160780
Wei J, Wu H, Zhang H, Li F, Chen S, Hou B, Shi Y, Zhao L, Duan H (2018) Anthocyanins inhibit high glucose-induced renal tubular cell apoptosis caused by oxidative stress in db/db mice. Int J Mol Med 41:1608–1618. https://doi.org/10.3892/ijmm.2018.3378
Williamson G, Clifford MN (2017) Role of the small intestine, colon and microbiota in determining the metabolic fate of polyphenols. Biochem Pharmacol 139:24–39. https://doi.org/10.1016/j.bcp.2017.03.012
Wu IW, Gao SS, Chou HC, Yang HY, Chang LC, Kuo YL, Dinh MCV, Chung WH, Yang CW (2020) Integrative metagenomic and metabolomic analyses reveal severity-specific signatures of gut microbiota in chronic kidney disease. Theranostics 10(12):5398–5411. https://doi.org/10.7150/thno.41725
Xu D, Hu MJ, Wang YQ, Cui YL (2019) Antioxidant activities of quercetin and its complexes for medicinal application. Molecules 24(6):1123. https://doi.org/10.3390/molecules24061123
Yamada Y, Takano Y, Abe J, Hibino M, Harashima H (2020) Therapeutic strategies for regulating mitochondrial oxidative stress. Biomolecules 10(1):83. https://doi.org/10.3390/biom10010083
Yang H, Song Y, Liang YN, Li R (2018) Quercetin treatment improves renal function and protects the kidney in a rat model of adenine-induced chronic kidney disease. Med Sci Monit 24:4760–4766. https://doi.org/10.12659/MSM.909259
Ye T, Zhen J, Du Y, Zhou JK, Peng A, Vaziri ND, Mohan C, Xu Y, Zhou XJ (2015) Green tea polyphenol (-)-epigallocatechin-3-gallate restores Nrf2 activity and ameliorates crescentic glomerulonephritis. PLoS ONE 10(3):e0119543. https://doi.org/10.1371/journal.pone.0119543
Ye T, Yang X, Liu H, Lv P, Lu H, Jiang K, Peng E, Ye Z, Chen Z, Tang K (2021) Theaflavin protects against oxalate calcium-induced kidney oxidative stress injury via upregulation of SIRT1. Int J Biol Sci 17(4):1050–1060. https://doi.org/10.7150/ijbs.57160
Yi L, Ma S, Ren D (2017) Phytochemistry and bioactivity of Citrus flavonoids: a focus on antioxidant, anti-inflammatory, anticancer and cardiovascular protection activities. Phytochem Rev 16:479–511. https://doi.org/10.1007/s11101-017-9497-1
Zamora-Ros R, Biessy C, Rothwell J, Monge A, Lajous M, Scalbert A, López-Ridaura R, Romieu I (2018) Dietary polyphenol intake and their major food sources in the Mexican Teachers’ Cohort. Brit J Nutr 120:1–8. https://doi.org/10.1017/S0007114518001381
Zhang J, Yang S, Li H, Chen F, Shi J (2017) Naringin ameliorates diabetic nephropathy by inhibiting NADPH oxidase 4. Eur J Pharmacol 804:1–6. https://doi.org/10.1016/j.ejphar.2017.04.006
Zhang H, Hassan YI, Liu R, Mats L, Yang C, Liu C, Tsao R (2020) Molecular mechanisms underlying the absorption of aglycone and glycosidic flavonoids in a Caco-2 BBe1 cell model. ACS Omega 5(19):10782–10793. https://doi.org/10.1021/acsomega.0c00379
Zhao Q, Zhang Y, Wang G, Hill L, Weng JK, Chen XY, Xue H, Martin CJSA (2016) A specialized flavone biosynthetic pathway has evolved in the medicinal plant. Scutellaria Baicalensis Sci Adv 2(4):e1501780. https://doi.org/10.1126/sciadv.1501780
Zhao J, Yang J, Xie Y (2019) Improvement strategies for the oral bioavailability of poorly water-soluble flavonoids: an overview. Int J Pharm 570:118642. https://doi.org/10.1016/j.ijpharm.2019.118642
Zhou T, Luo M, Cai W, Zhou S, Feng D, Xu C, Wang H (2018) Runt-related transcription factor 1 (RUNX1) promotes TGF-beta-induced renal tubular epithelial-to-mesenchymal transition (EMT) and renal fibrosis through the PI3K subunit p110delta. EBioMedicine 31:217–225. https://doi.org/10.1016/j.ebiom.2018.04.023
Zhu X, Shi J, Li H (2018) Liquiritigenin attenuates high glucose-induced mesangial matrix accumulation, oxidative stress, and inflammation by suppression of the NF-kappaB and NLRP3 inflammasome pathways. Biomed Pharmacother 106:976–982. https://doi.org/10.1016/j.biopha.2018.07.045
Zoccali C, Vanholder R, Massy ZA, Ortiz A, Sarafidis P, Dekker FW, Fliser D, Fouque D (2017) The systemic nature of CKD. Nat Rev Nephrol 13(6):344–358. https://doi.org/10.1038/nrneph.2017.52
Zuo AR, Dong HH, Yu YY, Shu QL, Zheng LX, Yu XY, Cao SW (2018) The antityrosinase and antioxidant activities of flavonoids dominated by the number and location of phenolic hydroxyl groups. Chin Med 13:51. https://doi.org/10.1186/s13020-018-0206-9
Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grant number 32072149, 32102006); Key Research and Development Program in Zhejiang province (Grant Number 2019C02070, 2021C02019); and Alexander von Humboldt foundation, Germany.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Lin, Y., Fang, J., Zhang, Z. et al. Plant flavonoids bioavailability in vivo and mechanisms of benefits on chronic kidney disease: a comprehensive review. Phytochem Rev 22, 1541–1565 (2023). https://doi.org/10.1007/s11101-022-09837-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11101-022-09837-w