INTRODUCTION
Kidney disease is quietly becoming a hidden global epidemic, growing at the third fastest rate among global causes of death, and is projected to become the fifth leading cause of death by 2040. Acute kidney injury (AKI) occurs in about 10%-15% of hospitalized patients and up to 50% in the intensive care unit. With its rapid onset and high mortality rate, AKI is an acute and critical condition of kidney disease.[] Chronic kidney disease (CKD) is a progressive condition characterized by changes in the structure and function of the kidneys due to a variety of causes. The global burden of CKD is enormous and growing: approximately 10% of the world’s adult population is affected by some form of CKD, resulting in 1.2 million deaths and 28.0 million life expectancy lost each year.[] Quercetin, a widely consumed flavonoid,[] has been reported to play an inhibitory role in AKI[,] and chronicrenal fibrosis.[,] It is now clear that the renal protective effects of quercetin are attributed to its antioxidant, anti-inflammatory, and anti-apoptotic properties, making it a potential therapeutic drug for various kidney-related diseases.[] Over the past decade, the renoprotective effect of quercetin on AKI has been studied in a wide range of experimental models, including ischemic AKI,[] cisplatin-induced AKI,[] and coronavirus disease 2019 (COVID-19) related AKI.[,] Mechanistic studies have shown that quercetin effectively attenuates AKI by inhibiting renal inflammation, ferroptosis, and cell apoptosis. Quercetin has also been reported to be renoprotective in a number of CKD cases, including ureteral obstruction,[] diabetic nephropathy,[,] cyclosporine A nephropathy,[] and ferric nitrilotriacetate nephropathy.[] The anti-inflammatory properties of quercetin are attributed to its ability to inhibit epithelial-to-mesenchymal transition (EMT), inflammation, and cellular senescence.[] However, quercetin has poor water solubility, low absorption, and limited bioavailability. In human studies, its oral bioavailability is about 24%, which is further reduced in rats by around 16%.[,] When taken in capsule form, the bioavailability in humans can be as low as 1%.[,] Despite these challenges, quercetin is well tolerated and safe. Human studies have shown that the use of doses up to 1000 mg/day does not cause adverse effects on blood parameters, liver and kidney function, hematology, or serum electrolytes, even when it is taken for several months.[,] Current advances in nanotechnology have resulted in the formulation of quercetin nanoparticles that have overcome their poor water solubility and improved their therapeutic efficacy on kidney disease.[]
QUERCETIN IS THE MAIN INGREDIENT IN MANY HERBS AND REMEDIES FOR TREATING KIDNEY DISEASE
According to traditional Chinese medicine (TCM) theory, the kidney is the foundation of innate nature and is the storage place of the body’s “innate essence”. The kidney is also the foundation of five organs and is the place where “vital energy”, the driving force of human life activities, is produced and stored. Thus, the kidney has many functional activities, such as storing essence, mastering growth, development, reproduction, mastering water, and holding the “qi”, Kidney diseases may occur due to the internalization of excessive pathogenic factors based on the deficiency of the “qi” and the imbalance of “the yin and yang”. Excessive pathogenic factors can be either exogenous or endogenous and mainly include retention of phlegm and morbid fluid, retention of dampness, and blood stasis. Therefore, the treatment of kidney diseases is based on tonifying the kidney and eliminating pathogenic factors, especially clearing “heat” (inflammation), draining dampness, purging turbidity, and activating blood (increasing blood circulation).
Quercetin is a main active ingredient in a variety of heat-clearing, detoxifying, and dampness-relieving herbs, such as Rhizoma Coptidis,[] Smilax glabra Roxb,[] Abelmoschus manihot (Linn.) Medicus (A. Manihot),[] and Lobeliae Chinensis Herba.[] It is also the main active ingredient in many kidney tonic herbs, such as Astragali Radix,[] Semen Cuscutae,[] and Cornus officinalis.[] In addition, quercetin is the main active component of a variety of TCM formulas for the clinical treatment of kidney disease. Liuwei Dihuanng pill (LWDH) is a popular Chinese medical prescription that has proven to be effective in the treatment of CKD. Xie et al. used Cytoscape to construct a drug-ingredient-target network to clarify the active ingredients of LWDH. The results showed that quercetin is the central component of LWDH.[] Quercetin is also an effective component of the Fufang Shenhua tablet, which is a TCM preparation with a long-term therapeutic effect on CKD.[] Again, quercetin is a main active ingredient in HuangZhi YiShen capsule, a Chinese patent herbal drug with therapeutic effects on diabetic kidney disease.[] Yishen Qingli Heluo Granule (YQHG) is a TCM compound for the clinical treatment of CKD, and quercetin is considered the main active compound of YQHG based on compound-target network interactions.[]
THERAPEUTIC EFFECTS AND MECHANISMS OF QUERCETIN ON AKI
AKI is a nephrotic syndrome characterized by a rapid decline in glomerular filtration, which may mostly be induced by sepsis, ischemia-reperfusion injury, nephrotoxic drugs, and even SARS-CoV-2 infection.[,] Quercetin may exert its therapeutic effects on AKI by inactivating pro-inflammatory macrophages and blocking cell death pathways [Figure 1]. A previous study reported that treatment with quercetin strikingly improved renal dysfunction and ameliorated tubular injury caused by lipopolysaccharide (LPS) in mice. Quercetin pretreatment obviously restrains LPS-triggered cell apoptosis and inflammation by upregulating Sirt1 while suppressing nuclear factor kappa-B (NF-κB) activation.[] Quercetin can inhibit ferroptosis by reducing the levels of activation transcription factor 3 (ATF3) and lipid reactive oxygen species and by increasing the levels of glutathione peroxidase 4, thereby ameliorating AKI induced by ischemia-reperfusion or folic acid.[] Quercetin can also inhibit renal ischemia-reperfusion injury by reducing macrophage infiltration and inducible nitric oxide synthase activity.[] Quercetin can significantly reduce the serum levels of creatinine, blood urea nitrogen, interleukin 1β (IL-1β), IL-6, and tumor necrosis factor-α in a cisplatin-induced AKI model.[] Further studies have also revealed that quercetin exerts its renal protective effects on AKI by suppressing the activation of pro-inflammatory macrophages through a Mincle-dependent mechanism.[] AKI is also common in critically ill COVID-19 patient.[] In SARS-CoV-2 N protein-induced AKI, treatment with quercetin significantly inhibits the release of a damage-associated molecular pattern molecule high-mobility group protein 1 and inactivates M1 pro-inflammatory macrophages while promoting reparative M2 macrophage responses by suppressing Mincle-Syk/NF-κB signaling in vivo and in vitro [Figure 1].[] Using network pharmacology and molecular docking, quercetin can interact with SARS-CoV-2 proteins to exert its potential therapeutic effect on COVID-19.[] This finding suggests that quercetin may directly interact with SARS-CoV-2 to protect against COVID-19 AKI. Indeed, quercetin may serve as a SARS-CoV-2 inhibitor by binding to the active sites of SARS-CoV-2 main protease 3CL and ACE2, thus suppressing the viral life cycle.[] Our other study demonstrated that treatment with quercetin can effectively inhibit SARS-CoV-2 N-induced AKI in diabetic db/db mice by blocking the binding of SARS-CoV-2 N protein to Smad3, thus inhibiting SARS-CoV-2 N-induced tubular epithelial cell (TEC) death through the Smad3-p16-dependent G1 cell-cycle arrest mechanism [Figure 1].[] Taken together, quercetin is a therapeutic agent for SARS-CoV-2 N protein-induced AKI in db/db mice and may inhibit AKI by switching M1 to M2 macrophage activation, which may be associated with the inactivation of Mincle signaling [Figure 1].[] These novel findings may well explain the efficacy and mechanisms of TCM-based therapies for COVID-19 patients.
Figure 1.
Therapeutic mechanisms of quercetin in AKI. Quercetin exerts its therapeutic effect on AKI by inactivating pro-inflammatory macrophages and inhibiting renal inflammation through the Mincle-Sky/NFκB-dependent mechanisms and by blocking the cell death pathways, including TGF-β/Smad3-mediated G1 cell-cycle arrest and ATF3-dependent ferroptosis. Red arrows represent the pathogenic or positive regulatory mechanisms, while blue lines indicate the protective or negative regulatory pathways during AKI. AKI, acute kidney injury; TGF-β, transforming growth factor-β; ATF3, activation transcription factor 3; NF-κB, nuclear factor kappa B.
THERAPEUTIC EFFECTS AND MECHANISMS OF QUERCETIN ON RENAL FIBROSIS
Inhibition of EMT
The burden of CKD on health, society, and the economy is substantial worldwide. CKD is characterized by a gradual and irreversible decline in kidney function, indicated by a progressive reduction in the glomerular filtration rate (GFR).[] Renal fibrosis represents the end stage of CKD, encompassing conditions such as chronic glomerulonephritis, obstructive nephropathy, and diabetic nephropathy, and it is also a primary cause of progressive renal failure.[] Renal fibrosis is characterized by tissue sclerosis or scar formation resulting from excessive extracellular matrix (ECM) deposition during a chronic inflammatory response triggered by various stimuli.[] The ECM is a complex mixture of cellular and non-cellular components present in tissues and organs, forming a three-dimensional structural network. The ECM contains nearly a thousand proteins, with its main components being structural proteins, such as collagen, elastin, fibronectin, and laminin.[]
During fibrogenesis, EMT occurring in renal TEC can trigger the process of renal fibrosis. EMT is described as a biological process in which epithelial cells lose their characteristic phenotypes, such as E-cadherin expression, while expressing mesenchymal cell markers, such as α-smooth muscle actin.[] Transforming growth factor-β (TGF-β) signaling is a key pathway leading to progressive renal fibrosis.[] Increasing evidence demonstrates that quercetin exerts its anti-fibrotic effect on CKD by inhibiting the fibrotic pathways, such as TGF-β, Sonic Hedgehog, and mTOR signaling, while activating the SIRT1-PINK1/Parkin pathway [Figure 2]. It has been reported that treatment with quercetin can inhibit renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO) by suppressing the EMT process via the TGF-β-dependent mechanism.[,] Quercetin can also effectively suppress EMT, ECM deposition, and cellular proliferation by inhibiting the hyperactive Hedgehog pathway or amphiregulin (ARGR)/epidermal growth factor receptor (EGFR) signaling.[,] In diabetic nephropathy, quercetin reveals its suppressive effect on EMT and renal fibrosis by inactivating the mTORC1/p70S6K pathway.[]
TGF-β is a key mediator in renal fibrosis.[] TGF-β, produced by various cells in an inactive form, is responsible for regulating ECM remodeling, which is a central pathway of fibrosis. Inhibition of TGF-β1 or its downstream signaling pathways substantially limits renal fibrosis in a wide range of disease models.[] Increasing evidence shows that quercetin exerts its anti-fibrotic effect on CKD by targeting TGF-β signaling [Figure 2]. A study showed that quercetin inhibits asymmetric dimethylarginine (ADMA)-induced TGF-β expression via the PERK-CHOP- and IRE1-JNK-mediated pathways, thereby preventing renal fibrosis.[] Quercetin also significantly inhibits TGF-β-induced EMT and ameliorates renal fibrosis in vivo and in vitro.[,] A recent study demonstrated that quercetin has anti-fibrotic effects on CKD patients by suppressing the TGF-β1-induced expression of miR-21.[] The anti-fibrotic effects of quercetin on CKD by targeting TGF-β signaling are also found in a variety of animal models, including glomerulosclerosis and diabetic nephropathy.[,] In addition, quercetin treatment can ameliorate diabetic renal damage by inhibiting CTGF expression.[]
Figure 2.
Anti-fibrotic mechanisms of quercetin in renal fibrosis. Quercetin exerts its anti-fibrotic effect by inhibiting the fibrotic pathways, such as TGF-β/Smad, Sonic Hedgehog, ARGR/EGFR, and ADMA signaling, while activating the SIRT1-PINK1/Parkin pathway. Red arrows represent the pathogenic or positive regulatory pathways, while blue lines indicate the protective or negative regulatory pathways during renal fibrosis. EGFR, epidermal growth factor receptor; ADMA, asymmetric dimethylarginine; ARGR, amphiregulin.
Anti-inflammation
Inflammation occurs throughout the fibrotic process. Renal injuries promote the recruitment of inflammatory cells and the release of related cytokines, chemokines, and ROS.[,,] It has been reported that quercetin can attenuate tubulointerstitial inflammation and fibrosis in vivo and in vitro by inhibiting Hsp70- or Hsp90-mediated exosome release and intercellular communication.[] Quercetin can also inhibit M1 macrophage polarization and reduce the excessive accumulation of ECM to improve interstitial fibrosis in the kidneys via the NF-κB/IRF5 signaling pathway and the TGF-β/Smad pathway.[] In lupus nephritis, quercetin can ameliorate pathological deterioration by reversing IL-33-induced inflammation and fibrosis.[] In diabetic nephropathy, histopathological findings revealed that treatment with quercetin significantly reduced inflammatory cell infiltration and renal fibrosis by suppressing the expression of COX-2 protein in STZ-induced diabetic rats.[] Moreover, quercetin serves as a potent inhibitor of YY1. Its capacity to mitigate tissue inflammation is associated with the inhibition of the YY1-mediated IL-6/STAT-3 pathway, resulting in an improvement in renal fibrosis associated with diabetic nephropathy.[]
Anti-cell senescence
Increasing evidence shows that cellular senescence may trigger renal fibrosis in CKD patients.[] Quercetin can effectively attenuate cellular senescence and renal interstitial fibrosis by enhancing mitophagy through the activation of the SIRT1-PINK1/Parkin pathway in vivo and in vitro.[] Treatment with quercetin and Dasatinib alleviates renal senescence and reduces the progression of renal fibrosis in unilateral ischemia-reperfusion injury and multiple cisplatin-treatment murine models.[]
Inhibition of macrophage-myofibroblast transition (MMT)
TGF-β regulates renal fibrosis through canonical and noncanonical TGF-β signaling.[] MMT has recently been discovered as a newly identified pathway for ECM-producing myofibroblasts through the TGF-β/Smad3-dependent mechanism.[,] Further studies have demonstrated that Src and Pou4f1, which serve as direct Smad3 target genes, are essential for MMT-driven fibrotic diseases.[,] Treatment with clopidogrel, a P2Y12 inhibitor, is capable of inhibiting TGF-β/Smad3-mediated MMT and progressive renal fibrosis in vivo and in vitro.[] This finding suggests that quercetin may act as a Smad3 inhibitor capable of inhibiting renal fibrosis by blocking the MMT process, which may provide new insight into quercetin in the treatment of renal fibrosis.
CONCLUSION AND FUTURE PERSPECTIVES
Quercetin has anti-inflammatory, anti-fibrotic, anti-aging, antioxidant, and anti-apoptotic properties. Current advances in research on the efficacy of quercetin have provided insight into the mechanism of action of quercetin as an anti-inflammatory and anti-cell death agent in AKI. In terms of renal fibrosis, quercetin blocks fibrotic pathways and ameliorates inflammation and cellular senescence. TGF-β/Smad3 can mediate MMT and progressive renal fibrosis. Quercetin has been shown to be an inhibitor of Smad3 and may have a blocking effect on the MMT process, which needs to be confirmed by further studies. In addition, the mechanisms of the AKI-CKD transition have received increasing attention in recent years. However, whether quercetin can inhibit the AKI-CKD transition requires further investigation. Although numerous studies have confirmed that quercetin can effectively treat a variety of kidney diseases, the mechanism has not been well studied, and more research is needed to identify specific targets. Currently, the therapeutic effects of quercetin are mostly experimental, and clinical trials are required to validate these experimental notions. Furthermore, quercetin has poor water solubility and low oral bioavailability, which limit its clinical therapeutic effect. Thus, there is an urgent need to improve the properties and delivery systems of quercetin to make it a suitable therapeutic agent for clinical use.
Financial support and sponsorship
This study was supported by grants from the National Natural Science Foundation of China (Grant No. 82304910, No. 82374384) and the Natural Science Foundation of Hubei Province, China (Grant No. 2024AFB925, No. 2022CFD021).
Author contributions
Wang WB: Conceptualization, Writing—Original draft preparation. Wu WJ: Conceptualization, Writing— Reviewing and Editing. All authors have reviewed and approved the final version of the manuscript.
Ethics approval and consent to participate
Not applicable.
Conflict of interest
The authors declare no competing interest.
Data availability statement
Not applicable.
How to cite: Wang WB, Wu WJ. Therapeutic Effects of Quercetin on Renal Fibrosis and Injury. Integr Med Nephrol Androl. 2025;12:e24-00051. doi: 10.1097/IMNA-D-24-00051
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