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Anthraquinones from Rheum officinale Ameliorate Renal Fibrosis in Acute Kidney Injury and Chronic Kidney Disease
Authors Feng HY, Wang YQ, Yang J, Miao H, Zhao YY, Li X
Received 7 March 2025
Accepted for publication 13 June 2025
Published 6 July 2025 Volume 2025:19 Pages 5739—5760
DOI https://doi.org/10.2147/DDDT.S521265
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Solomon Tadesse Zeleke
Hao-Yu Feng,1,2,* Yi-Qi Wang,2,* Jianhua Yang,3,4 Hua Miao,1,2 Ying-Yong Zhao,1,2 Xiaojuan Li1
1School of Pharmaceutical Sciences, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China; 4Xinjiang Key Laboratory of Clinical Drug Research, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Ying-Yong Zhao, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China, Tel/Fax +86 571 61768528, Email [email protected] Xiaojuan Li, School of Pharmaceutical Sciences, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310001, People’s Republic of China, Email [email protected]
Abstract: Renal diseases including acute kidney injury (AKI) and chronic kidney disease (CKD) has become a significant public health concern due to its high morbidity and mortality. Rheum officinale Baill (Polygonaceae) exhibits diuretic, renoprotective, lipid-lowering, anti-inflammatory, and antifibrotic properties. Accumulating evidence has highlighted the anthraquinones in R. officinale as key components contributing to its renoprotective effects. The available information on R. officinale was searched by several electronic database such as PubMed, Web of Science, Springer, ScienceDirect, etc. This review summarizes the anthraquinones and their renoprotective effects in R. officinale, evaluating its clinical potential for managing renal disease including AKI and CKD. Studies demonstrate that R. officinale contains bioactive components such as anthraquinones, stilbenes, phenylbutazones, and tannins. This review discusses the renoprotective effects of R. officinale, including improvements in renal function, reduction of podocyte damage, and inhibition of renal fibrosis. These effects are mediated through the regulation of pro-inflammatory (IκB/NF-κB and Keap1/Nrf2), pro-fibrotic (TGF-β 1/Smad and Wnt/β-catenin), AMP-activated protein kinase and phosphoinositide 3-kinase signaling pathways in AKI and CKD. Additional mechanisms include modulation of anti-ageing Klotho expression, autophagy, and apoptosis. These findings expand the understanding of the therapeutic effects on AKI and CKD of R. officinale and provide valuable information on its clinical application in traditional Chinese medicine. This review presents a concept-driven therapeutic strategy for renal disease management.
Keywords: acute kidney injury, chronic kidney disease, Rheum officinale, anthraquinones, oxidative stress and inflammation, TGF-β/Smad
Introduction
Acute kidney injury (AKI) and chronic kidney disease (CKD) are important clinical problems and global health burdens with rising prevalence.1,2 Substantial studies have demonstrated that increasing incidence of AKI and kidney injury required dialysis and kidney transplantation worldwide.3,4 This increase has coincided with increasing incidence of end-stage renal disease (ESRD), which has exceeded that expected based upon morbidity and mortality of CKD.5,6 AKI is a clinical symptom of sudden loss of excretory kidney function that leads to long-term kidney damage.7,8 AKI is characterized by a rapid decline in renal function, leading to the accumulation of uremic toxins, such as creatinine and urea, and a reduction in urine output.9 AKI can be caused by various initial injuries, including ischemia-reperfusion injury (IRI), cardiovascular surgery, radiographic contrast agents, and sepsis.10–12 CKD has become an increasingly significant public health problem due to its high morbidity and mortality, with a prevalence of 8–16% worldwide and more than 850 million people.13–15 Considerable evidence suggests that AKI is closely associated with the progression of CKD and, eventually, ESRD.16–19 Many patients who survive an episode of AKI subsequently develop CKD, which can progress to ESRD.20–23 The number of patients requiring dialysis therapy and kidney transplantation continues to increase worldwide owing to the lack of effective treatments for CKD.24 Furthermore, no curative treatments for AKI and CKD have been established.25,26
In clinical practice, traditional Chinese medicine (TCM) has long been used as an important therapy for the prevention and treatment of renal disease.27–31 TCM demonstrates unique advantages due to its multi-component, multi-pathway, and multi-target characteristics.32,33 Rheum officinale Baill. (Polygonaceae), known for its heat-clearing, purging, blood-cooling, detoxifying, and hemostatic properties, is a widely used herb for the treatment of renal disease in Asia, offering a range of pharmacological effects that may delay disease progression.34–37 R. officinale contains various compounds, including anthraquinones, anthracenes, tannins, and stilbenes. Anthraquinones, such as rhein, emodin, chrysophanol, physcion, and aloe-emodin, are among the most important active components of R. officinale and play a critical role in improving renal function.38–41 A growing body of research has highlighted the bioactive compounds of R. officinale in mitigating renal fibrosis by inhibiting the Wnt/β-catenin, inhibitor of kappa B (IκB)/nuclear factor kappa B (NF-κB), and Wnt/β-catenin signaling pathways, as well as by enhancing the kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway.42,43 This review aims to summarize the therapeutic effects of the anthraquinones from R. officinale for AKI and CKD, and to further elucidate their underlying molecular mechanisms, including antioxidative, anti-inflammatory, anti-fibrotic, and anti-apoptotic effects.
Renoprotective Components in R. officinale
R. officinale, a group of plants belonging to the genus Rheum L. in the family Polygonaceae, is one of the oldest and best-known Chinese herbal medicines, with a long history of medicinal use in China and other Asian countries, dating back to the “Shen Nong Ben Cao Jing”.44 To date, many compounds have been identified from R. officinale45,46 (Figure 1, Tables 1 and 2), which can be mainly classified into seven categories: anthraquinones, anthracenes, stilbenes, tannins, phenylbutanoids, chromones, and other components such as organic acids and volatile constituents47,48 (Figure 1, Tables 1 and 2). The main anthraquinone components of R. officinale and their wide range of pharmacological activities are described as follows.
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Table 1 Chemical Structures of Anthraquinones (1–21) and Anthranones (22–46) in R. officinale |
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Table 2 Chemical Structures of Stilbenoids (47–60) and Tannins (61–77) in R. officinale |
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Figure 1 The structures of chemical components of R. officinale. Compounds 1–21 indicate anthraquinones, Compounds 22–46 indicate anthranones, Compounds 47–60 indicate stilbenoid, and Compounds 61–77 indicate tannin in R. officinale. |
Anthraquinones
Anthraquinones are the main components of R. officinale, comprising 1.5–4.0% of its total content.49 Anthraquinones, including rhein, emodin, chrysophanol, physcion, and aloe-emodin, are the primary characteristic and pharmacodynamic components of R. officinale.50 The anthraquinones in medicinal plants of the genus Rheum are mainly emodin-type anthraquinones, with hydroxyl groups distributed on the benzene ring on both sides. Over 30 free and combined anthraquinones have been isolated and identified from R. officinale. Free anthraquinones include rhein, emodin, chrysophanol, physcion, aloe-emodin, isoemodin, chrysaron, isoemodin, and urachic acid D46 (Figure 1, Tables 1 and 2).
Rhein
Rhein (1,8-dihydroxy-3-carboxylic anthraquinone), an anthraquinone monomer, exhibits a wide range of pharmacological activities, including anti-inflammatory,51 antioxidant,52 antitumor,53 antifibrotic,54 lipid-regulating,55 glucose-lowering,56 antiviral, and antibacterial effects.57 Previous studies have demonstrated that rhein protects against renal fibrosis in diabetic kidney disease (DKD). Its beneficial effects on DKD are mediated through the amelioration of transforming growth factor beta 1 (TGF-β1) levels, oxidative stress reduction, and renal fibrosis attenuation.58
Emodin
Emodin (1,3,8-trihydroxy-6-methylanthraquinone), a key monomer derived from R. officinale, exhibits a broad spectrum of pharmacological effects, including antitumor,43,44 antimicrobial,45 antioxidant,46 anti-inflammatory47 and antifibrotic48,49 activities. Additionally, emodin has been shown to reduce hypertension, lower blood lipid levels, enhance microcirculation, and protect against liver and kidney injury. As a validated renoprotective agent in DKD rat models, emodin was found to reduce proteinuria and alleviate renal fibrosis, functioning as a natural regulator without influencing blood glucose levels.59 Furthermore, emodin attenuates renal IRI through its anti-inflammatory effects in rats and mice, which are critical for mitigating AKI.
Chrysophanol
Chrysophanol (1,8-dihydroxy-3-methyl-anthraquinone), the most abundant free anthraquinone compound in R. officinale,60 exhibits a wide array of pharmacological effects, including anticancer, antiviral, antidiabetic, anti-inflammatory, antibacterial, hypolipidemic, hepatoprotective, neuroprotective, anti-ulcer, and anti-obesity activities.61,62 Additionally, chrysophanol has been shown to protect against nervous system disorders by enhancing the activity of antioxidant enzymes and mitigating cellular damage caused by oxygen-free radicals.63
Physcion
Physcion (1,8-dihydroxy-3-methoxy-6-methyl-anthraquinone), also known as parietin, is an anthraquinone derivative isolated and characterized from terrestrial and marine sources. As a primary active component of R. officinale, physcion has attracted significant attention for its remarkable pharmacological activities.64 Notably, physcion exhibits neuroprotective effects by suppressing inflammatory responses following cerebral ischemia and mitigating nerve damage caused by reperfusion.65 Furthermore, physcion demonstrates antitumor activity against various cancer cell types by inhibiting cell proliferation, inducing apoptosis, and arresting the cell cycle.58
Aloe-Emodin
Aloe-emodin (1,8-dihydroxy-3-[hydroxymethyl]-anthraquinone), an active compound in R. officinale, has been widely utilized in TCM for the treatment of various diseases.59–61 Aloe-emodin has extensive renoprotective effects. In addition, it has received significant attention for its cardiovascular protective, hepatoprotective, antitumor, antibacterial, antifungal, antiviral, anti-inflammatory, immune-regulatory, and laxative properties.66–68
Stilbene
Stilbene is a compound characterized by two benzene rings connected by a vinyl group. Stilbenes are key components of R. officinale and exhibit various pharmacological activities, including anticancer, antibacterial, antioxidative, anti-inflammatory, antidiabetic, anti-ageing, neuroprotective, and hepatoprotective effects.69 Resveratrol (3,5,4-trihydroxystilbene), a naturally occurring polyphenolic phytoprotectant found in many plants and products, is also present in R. officinale. Resveratrol has demonstrated numerous beneficial properties, including anticancer,66 antioxidative,67 anti-inflammatory68,69 and neuroprotective70,71 activities. The stilbenes in R. officinale act as effective antioxidants, primarily through the action of resveratrol, which scavenges oxygen radicals.70 Additionally, resveratrol has been reported to protect against AKI and CKD.71,72
Anthrones and Dianthrones
Anthracenes and dianthrones are characteristic constituents of R. officinale and are primarily responsible for its diarrhea-inducing effects.47 Numerous anthracene derivatives have been isolated from R. officinale.73 Among these, sennosides can be metabolized in vivo into anthraquinones, which exhibit potent laxative properties.
Molecular Mechanism of Renoprotective Effects of Anthraquinones from R. officinale in AKI
AKI can result from various pathogenic factors, including renal hypoperfusion, urethral obstruction, rapidly progressive glomerular disease, acute vasculitis, and acute interstitial nephritis.7,8,74,75 Based on etiology, AKI can be classified into drug-induced AKI, septic AKI, and IRI-induced AKI.9,10,76
Renal IRI, commonly occurring after renal transplantation and surgery, is a leading cause of AKI.77 Due to the kidney’s unique physiological structure and its central role in drug excretion, drug-induced AKI is particularly common, with acute tubular or tubulointerstitial injury being the most frequent cause.78,79 Septic AKI, associated with infection, represents a syndrome of acute functional impairment and organ damage and is the most prevalent form of AKI among intensive care unit patients.80 IRI-induced AKI arises from ischemia and hypoxia caused by blood supply interruption, followed by reperfusion, leading to further organ dysfunction.77
In recent years, the emergence of coronavirus disease 2019 (COVID-19) has shown AKI as a frequent complication of severe infection associated with high mortality rates.81,82 Alarmingly, only 30% of AKI patients regain full renal function after discharge.83 Given the complexity of AKI pathogenesis, multi-component extracts and isolated compounds derived from natural products present a promising alternative therapeutic strategy due to their multi-target mechanisms and established biosafety profiles.84–86 Modern medical studies have demonstrated that anthraquinones such as emodin and chrysophanol can alleviate kidney injury associated with AKI. This review focuses on the renoprotective effects of anthraquinones derived from R. officinale in treating AKI.
Emodin in Improving AKI
Mitochondria play a key role in various pathophysiological processes by regulating calcium homeostasis, cell signaling pathways, transcriptional regulation, and apoptosis.87–89 Increasing evidence indicates that mitochondria are central to the progression of AKI, which is pathologically characterized by sublethal and lethal damage to renal tubules, often leading to tubular cell death through regulatory necrosis or apoptosis.84,85,90 Studies have shown that stimulated mitochondrial biogenesis can reduce necrosis and improve renal function in AKI models.86,91 Mechanistically, apoptotic cell death in AKI involves both intrinsic and extrinsic pathways, with mitochondria serving as the central hub. During cellular stress, mitochondria become fragmented and exhibit increased membrane permeability, releasing cell-death-inducing factors.92
Previous studies have demonstrated that emodin alleviates IRI in the heart, brain, and small intestine of rats and mice through its anti-inflammatory effects.93 Emodin, a key active compound in R. officinale, exhibits antibacterial, anti-inflammatory, antioxidative, immunosuppressive, and antifibrotic properties.94–96 It has been shown to reduce mitochondria-mediated apoptosis, inhibit excessive production of mitochondrial reactive oxygen species (ROS), and accelerate the recovery of adenosine triphosphate (ATP) both in vivo and in vitro (Table 3). Emodin also prevents mitochondrial fission and restores the balance of mitochondrial dynamics.97 Specifically, emodin improves and prevents IRI-induced renal injury by regulating mitochondrial homeostasis in renal tubular epithelial cells, restoring the dynamic equilibrium of mitochondrial fusion and fission, and protecting these cells from IRI-induced apoptosis.98
A randomized clinical trial revealed that emodin reduces glucose regeneration in renal tubular cells and ATP levels in epithelial mitochondria.99 Additionally, emodin restores the dynamic balance of mitochondrial fusion and fission by inhibiting calcium/calmodulin-dependent protein kinase II activity and downregulating the phosphorylation of dynamin-associated protein 1 at Ser616, a key regulator of mitochondrial fission. This regulation maintains mitochondrial homeostasis and reduces renal tubular cell death.
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Table 3 Molecular Mechanism of Renoprotective Effects of Anthraquinones in the Treatment of AKI |
Toll-like receptors (TLRs) also significantly recognize exogenous pathogens associated with septic AKI and are involved in numerous cellular processes activated during AKI.103,104 Experimental findings indicate that emodin inhibits the expression of inflammatory cytokines and TLR2 in lipopolysaccharide (LPS)-stimulated cells. By suppressing the TLR2-mediated NF-κB signaling pathway, emodin reduces the inflammatory response and protects against LPS-induced AKI.100 Furthermore, emodin inhibits the expression of TLR2 and NF-κB in normal rat kidney epithelial cells exposed to LPS.
Chrysophanol in Improving AKI
AKI is a major cause of renal IRI or hypoxia-reperfusion (H/R), as demonstrated in both cellular and mouse models.105,106 Evidence suggests that HK-2 cells are susceptible to renal IRI and are widely used as a cellular model for H/R injury to simulate acute renal IRI.107 Chrysophanol is effective in treating AKI.
Ferroptosis, an iron- and ROS-dependent lipid peroxidation process, is a distinct form of programmed cell death that differs from apoptosis and necrosis at both morphological and biochemical levels.108,109 It has received significant attention in AKI and CKD.110,111 Morphologically, ferroptosis is characterized by mitochondrial contraction, rupture of the mitochondrial membrane, increased membrane density, and reduction or disappearance of mitochondrial cristae.112,113 Biochemically, ferroptosis is associated with glutathione depletion and reduced glutathione peroxidase 4 (GPX4) activity. GPX4 is a critical enzyme that mitigates lipoxygenase activity and oxidative damage to phospholipids and cardiolipin.114 Iron imbalance, amino acid dysregulation, and excessive ROS production are closely linked to ferroptosis.115
Chrysophanol has been shown to inhibit H/R-induced apoptosis by downregulating the expression of cleaved phosphorylated c-Jun N-terminal kinase, caspase-3, and B-cell lymphoma-2-associated X (Bax) while upregulating B-cell lymphoma 2 (Bcl-2) expression. Furthermore, chrysophanol reduces H/R-induced endoplasmic reticulum (ER) stress by downregulating CCAAT-enhancer-binding protein homologous protein (CHOP) and phosphorylated inositol-requiring enzyme 1α.101 It also alleviates H/R-induced lipid ROS accumulation and ferroptosis, thereby mitigating renal cell damage by inhibiting ferroptosis. Chrysophanol may represent a novel therapeutic option for improving H/R-induced renal tubular cell injury by targeting ferroptosis (Table 3). As an antioxidant, chrysophanol enhances cellular antioxidant capacity by increasing the expression of GPX4 and solute carrier family 7 member 11 (SLC7A11).
Cisplatin, a widely used chemotherapy drug, is effective against solid tumors, such as ovarian, head, neck, and testicular germ cell cancers.116,117 However, its clinical application is limited by severe renal toxicity, which often leads to AKI.118 Clinically, AKI occurs in approximately one-third of patients receiving cisplatin chemotherapy. Cisplatin-induced AKI is associated with disruptions in various signal transduction pathways, leading to renal tubular injury, tubulointerstitial inflammation, and vascular damage.119,120 The underlying mechanisms involve DNA damage, apoptosis (both intrinsic and extrinsic), inflammation, and oxidative stress, with cell death and inflammatory pathology being the primary drivers of organ dysfunction.
Studies have shown that chrysophanol intervention significantly reduces serum creatinine and urea levels in cisplatin-induced AKI mouse models.102 Experimental findings confirm that chrysophanol alleviates renal function decline and pathological damage in cisplatin-induced AKI by inhibiting ROS production in damaged renal tubular epithelial cells. Chrysophanol emerges as a promising candidate for protecting renal tubular cells from cytotoxic damage and demonstrates significant therapeutic potential for cisplatin-induced AKI (Table 3).
Renoprotective Mechanism of Anthraquinones in CKD
CKD is one of the major causes of mortality worldwide due to renal failure.14 Current treatments, such as dialysis and kidney transplantation, are costly and not curative.121–123 Therefore, the treatment and management of renal diseases present a leading global challenge and necessitating innovative therapeutic strategies.124–126 Extensive studies have demonstrated that various naturally derived compounds can attenuate CKD through diverse molecular mechanisms.127–132 An increasing number of publications have highlighted that several anthraquinones ameliorate DKD, immunoglobulin A nephropathy (IgAN), and chronic glomerulonephritis by modulating key signaling pathways, including TGF-β1/small mothers against decapentaplegic (Smad), IκB/NF-κB, Keap1/Nrf2, Wnt/β-catenin, TLR4, AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), and glycogen synthase kinase-3 beta (GSK-3β) (Table 4, Figures 2 and 3).
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Table 4 Molecular Mechanism of Renoprotective Effects of Anthraquinones in the Treatment of CKD |
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Figure 2 The underlying renoprotective mechanisms of anthraquinones by inhibiting TGF-β1/Smad and Wnt1/β-catenin signaling pathways. AKI and CKD lead to the activations of profibrotic TGF-β1/Smad and Wnt/β-catenin signaling pathways. Treatment with anthraquinones such as rhein, chrysophanol, and rhein-8-O-glc could improve renal function and inhibit renal fibrosis by inhibiting the TGF-β1/Smad signaling pathway. Rhein could improve renal function and inhibit renal fibrosis by inhibiting the Wnt1/β-catenin signaling pathway. |
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Figure 3 The underlying renoprotective mechanisms of anthraquinones by regulating IƙB/NF-ƙB, Keap1/Nrf2 and PI3K/Akt/mTOR signaling pathways. AKI and CKD lead to the activations of proinflammatory IƙB/NF-ƙB and impaired Keap1/Nrf2 signaling pathways as well as PI3K/Akt/mTOR signaling pathways. Treatment with anthraquinones such as rhein, emodin, and chrysophanol could improve renal function and inhibit renal fibrosis by inhibiting oxidative stress and inflammation. Treatment with anthraquinones such as emodin and aloe-emodin could improve renal function, reduce podocyte damage, and inhibit renal fibrosis by regulating the PI3K/Akt/mTOR signaling pathway. |
Inhibition of DKD by Anthraquinones
Diabetes mellitus is the leading cause of ESRD worldwide.154 Poor glycemic control significantly contributes to the development and progression of complications in patients with diabetes mellitus.155 DKD, a common microvascular complication of diabetes, is primarily characterized by the proliferation of glomerular mesangial cells and the accumulation of extracellular matrix (ECM).124,156 However, the underlying pathogenesis of DKD remains incompletely understood. Several pathways have been implicated in the disease’s progression, including the hemodynamic pathway (involving the renin-angiotensin-aldosterone system and the urotensin system), pro-fibrotic and inflammatory cytokines such as TGF-β1 and tumor necrosis factor alpha (TNF-α), and kinases, such as protein kinase C (PKC) and Janus kinase pathway. Additionally, oxidative stress mediators play a critical role, particularly nicotinamide adenine dinucleotide phosphate oxidase (NOX).
Emerging research has revealed that several anthraquinones can attenuate DKD by targeting multiple signaling pathways. These include TGF-β1, NF-κB, and Ras-related C3 Botulinum toxin substrate 1 (Rac1); oxidative stress mediators such as NOX1; and regulatory pathways such as Keap1/Nrf2, interferon regulatory factor 4 (IRF4), glycogen synthase kinase-3 beta (GSK-3β), AMP-activated protein kinase (AMPK), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR) (Table 4, and Figures 2 and 3).
Amelioration of Podocyte Injury by the Components of Anthraquinones
Proteinuria is a significant clinical feature of DKD and is often associated with podocyte injury.157,158 Previous studies have suggested that a broad spectrum of compounds derived from TCM can reduce proteinuria levels and improve DKD outcomes.159–161 Controlled clinical studies have demonstrated that rhein is critical in inhibiting proteinuria and slowing the progression of DKD.162 The renoprotective effects of rhein in DKD are closely related to its regulation of nephrin gene expression, which is essential for maintaining podocyte integrity through nephrin protein. Experimental evidence suggests that rhein improves metabolic disorders and reduces fat mass by modulating the peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway, a key insulin sensitizer in treating type II diabetes.163 High glucose (HG) conditions notably decrease PPARγ expression at both mRNA and protein levels in podocytes, reducing podocin and nephrin expression and consequent podocyte injury.164 Thus, rhein exhibits significant therapeutic potential in DKD by preserving podocyte function.
Early evidence also demonstrates that emodin exerts renoprotective effects by inhibiting mesangial cell proliferation and epithelial–mesenchymal transition (EMT).146 Animal studies have shown that emodin reduces serum creatinine and urea levels and urinary albumin levels in DKD mice while improving pathological kidney injury. Additionally, emodin enhances renin activity and decreases markers of podocyte apoptosis and ER stress, such as glucose-regulated protein 78 (GRP78). Recent studies indicate that emodin reduces podocyte apoptosis in DKD by inhibiting the protein kinase R-like ER kinase-eukaryotic initiation factor 2 alpha (PERK-eIF2α) signaling pathway.142 Experimental results further demonstrate that emodin reduces proteinuria and alleviates renal fibrosis without affecting blood glucose levels in DKD rats.
Inhibition of Mesangial Cell Injury by the Components of R. officinale
Mesangial cells are crucial for maintaining renal filtration. Protecting these cells in patients with DKD can improve filtration, reduce proteinuria, and mitigate renal injury.165 Rhein has been shown to inhibit the proliferation of mesangial cells and the expression of ECM components induced by HG conditions. This effect is mediated by upregulating pro-apoptotic proteins Bax and caspase-3, leading to cell cycle arrest at the G1 phase and promoting apoptosis.166 Similarly, emodin inhibits HG-induced mesangial cell proliferation by inducing cell cycle arrest at the G1 phase through the upregulation of Bax and activation of caspases.167
Inhibition of TGF-β1/Smad Signalling Pathway by Anthraquinones
Extensive studies have identified TGF-β1 signaling as a central pathway in the progression of various renal diseases.168,169 Numerous publications have demonstrated the beneficial effects of rhein and related anthraquinones in mitigating DKD by inhibiting TGF-β1 signaling (Figure 2). For example, Guo et al reported that chrysophanol improved DKD by suppressing HG-induced growth and migration of human podocytes (AB8/13 cells) by inactivating the TGF-β1 signaling pathway.149 Similarly, Wang et al showed that emodin alleviated DKD in streptozotocin (STZ)-induced diabetic rats by reducing intrarenal expression of phosphorylated p38 MAPK and fibronectin.143 Furthermore, Zhang et al demonstrated that rhein-8-O-β-D-glucopyranoside (Rhein-8-O-Glc), a derivative of rhein, inhibited HG-induced apoptosis in human mesangial cells by regulating the lincRNA ANRIL/let-7a/TGF-β1/Smad signaling pathway.139 Jia et al found that rhein reduced plasma glucose, creatinine, cholesterol, triglyceride, and low-density lipoprotein levels while also downregulating protein expressions of TGF-β1 and fibronectin in db/db mice.133 These findings suggest that anthraquinones inhibit DKD progression by suppressing the TGF-β1/Smad signaling pathway, offering a promising therapeutic target for DKD treatment (Figure 2).
Regulation of Iƙb/NF-Ƙb and Keap1/Nrf2 Signalling Pathway by Anthraquinones
Inflammation plays a key role in the development of DKD. NF-κB regulates the expression of numerous genes involved in the inflammatory response, contributing significantly to experimental and clinical renal injury.170 Yang et al demonstrated that emodin downregulates fibronectin protein expression by inhibiting the NF-κB signaling pathway in DKD rats147 (Figure 3). Similarly, Xiong et al showed that rhein mitigates DKD by inhibiting ferroptosis and EMT by regulating the Rac1/NOX1/β-catenin signaling axis28 (Table 4).
Resveratrol has been shown to exert antioxidant effects by directly scavenging ROS or by enhancing the levels and activity of superoxide dismutase 2 in mitochondria. It also inhibits nicotinamide adenine dinucleotide phosphate oxidase activity, thereby reducing ROS production in DKD and protecting cells from oxygen-low-density lipoprotein-induced damage.171
Extensive studies have highlighted the importance of the Keap1/Nrf2 signaling pathway as a critical anti-inflammatory mechanism172 (Figure 3). Nrf2 regulates basal activity and the coordinated induction of genes encoding antioxidant and Phase 2 detoxifying enzymes and proteins. Yuan et al recently reported that chrysophanol downregulates Keap1 protein expression while preserving Nrf2 protein expression in DKD mice fed a high-sugar and high-fat diet and treated with streptozotocin. This effect was achieved by activating the Keap1/Nrf2 signaling pathway.42 Similarly, Ji et al found that emodin alleviates DKD by inhibiting ferroptosis through upregulation of Nrf2 expression in STZ-induced diabetic rats.148
Collectively, these findings suggest that anthraquinones can attenuate DKD by mitigating oxidative stress and inflammation (Figure 3).
Inhibition of Wnt/β-Catenin Signalling Pathway by Anthraquinones
The Wnt/β-catenin signaling pathway is an evolutionarily conserved cascade critical in regulating tissue development and maintaining homeostasis173,174 (Figure 2). Numerous studies have reported that Wnt/β-catenin signaling is activated in various CKDs, including DKD, adriamycin nephropathy, polycystic kidney disease, obstructive nephropathy, and chronic allograft nephropathy.175–178 Several TCMs have been shown to improve CKD by inhibiting the Wnt/β-catenin signaling pathway.179,180
Duan et al demonstrated that rhein downregulates the protein expression of GSK-3β and β-catenin, improving podocyte structure and function. This suggests that rhein ameliorates HG-induced podocyte injury through the Wnt1/β-catenin signaling pathway141 (Figure 2). In a subsequent study, the same research group showed that rhein preserves nephrin protein expression by inhibiting the expression of Wnt1, phosphorylated GSK-3β (p-GSK-3β), and phosphorylated β-catenin (p-β-catenin) in DKD mice.140 Additionally, Xiong et al reported that rhein mitigates DKD by inhibiting EMT by suppressing β-catenin signaling.43 These findings suggest that anthraquinones can attenuate DKD by inhibiting the Wnt/β-catenin signaling pathway (Figure 2).
Regulation of AMPK and PI3K/Akt/mTOR Signalling Pathways by Anthraquinones
Several anthraquinones have been shown to attenuate DKD by regulating key signaling pathways, including GSK-3β, AMPK, PI3K, Akt, and mTOR (Figure 3). Liu et al demonstrated that emodin alleviates renal injury and podocyte damage in DKD rats by modulating the AMPK/mTOR-mediated autophagy signaling pathway.144 Similarly, Jing et al reported that emodin protects against DKD in rats via the PI3K/Akt/GSK-3β and Bax/caspase-3 signaling pathways.59 These findings suggest that anthraquinones attenuate DKD through mechanisms involving AMPK and PI3K/Akt/mTOR signaling pathways (Figure 3).
Regulation of ER Stress and IRF4 Signalling by Anthraquinones
Several studies have demonstrated that the beneficial effects of anthraquinones are closely associated with ER stress and interferon regulatory factor 4 (IRF4) signaling. Tian et al reported that emodin mitigates podocyte apoptosis induced by ER stress by inhibiting the protein kinase RNA-like ER kinase (PERK) signaling pathway in DKD.142 Similarly, Yuan et al found that aloe-emodin ameliorates DKD by targeting IRF4 signaling.152
Rhein Blunted IgAN by Inhibiting TLR4 Signaling and Improved the Intestinal Barrier
An earlier study demonstrated that rhein protects against IgAN by inhibiting fibronectin expression in rats.181 TLR4, an intrinsic immune receptor, plays a significant role in the onset of various diseases. Chen et al showed that both rhein-preventive and rhein-therapeutic interventions alleviated glomerular pathological changes and tubulointerstitial fibrosis (TIF) in IgAN rats by inhibiting the expression of TLR4 and TGF-β1.134 Additionally, extensive studies have highlighted gut microbiota dysbiosis in patients with CKD.182–187 Peng et al reported that rhein preserves the protein expression of Zonula occludens-1 and occludin, repairs damaged tight junctions, and protects the intestinal barrier.135 These findings suggest that rhein ameliorates IgAN by inhibiting TLR4 signaling and protecting the intestinal barrier.
Rhein Abolished Chronic Glomerulonephritis by Improving Disorders of Endogenous Metabolites
Substantial studies have demonstrated that metabolomics has been extensively applied in CKD research to identify altered metabolic profiles and endogenous metabolites.188–190 Extensive studies have demonstrated that natural products ameliorated CKD by improving metabolic disorders.191–193 Chronic glomerulonephritis, a major cause of renal failure, significantly increases mortality in critically ill patients. Functional metabolomics analysis revealed that rhein modulated 16 biomarkers toward normal levels, involving six metabolic pathways: phenylalanine, tyrosine, and tryptophan biosynthesis; phenylalanine metabolism; arachidonic acid metabolism; the tricarboxylic acid (TCA) cycle; alanine, aspartate, and glutamate metabolism; and arginine and proline metabolism. The therapeutic effects of Rhein may be mediated by regulating amino acid metabolism, arachidonic acid metabolism, and the TCA cycle, contributing to anti-inflammatory, antioxidant, and immune-regulatory activities in chronic glomerulonephritis.194 Additionally, metabolomic analysis identified fatty acid oxidation disorders in unilateral ureteral obstruction (UUO) rats.195 These findings suggest that rhein ameliorates chronic glomerulonephritis by modulating amino acid and arachidonic acid metabolism.
Inhibition of Renal Fibrosis by Anthraquinones
Extensive studies have demonstrated that renal fibrosis is associated with various signaling pathways, including TGF-β1/Smad, IκB/NF-κB, Keap1/Nrf2, AMPK, and PI3K/Akt/mTOR (Table 4, Figures 2 and 3). Additionally, several other pathways, such as signal transducer and activator of transcription 3 (STAT3), high mobility group AT-hook 2 (HMGA2), Forkhead box O (FOXO), and Sonic hedgehog-glioma-associated oncogene 1 (Shh-GLI1), have also been implicated in the progression of renal fibrosis.
Inhibition of TGF-β1/Smad Signalling Pathway by Anthraquinones
Based on the UUO model, numerous studies have demonstrated that several anthraquinones can attenuate TIF by targeting the TGF-β1/Smad signaling pathway (Figure 2). For example, He et al reported that rhein inhibits the protein expression of TGF-β1, its type I receptor, alpha-smooth muscle actin (α-SMA), and fibronectin in the obstructed kidneys of UUO mice. In vitro experiments further confirmed that rhein reduces the expression of α-SMA and fibronectin in TGF-β1-induced NRK-49F cells.136 Dou et al showed that chrysophanol downregulates the protein expression of TGF-β1 and phosphorylated Smad3 while upregulating Smad7 in obstructed kidneys of UUO mice. However, the protein expression of Smad2, Smad4, and TGF-β1 receptors was not affected150 (Figure 2).
Xu et al revealed that emodin suppresses collagen deposition and reduces the protein expression of Smad3 and connective tissue growth factor in obstructed kidneys and NRK-49F cells. These effects were associated with the downregulation of the zeste homolog 2 (EZH2) enhancer and decreased trimethylation of histone H3 on lysine 27. Inhibition of EZH2 using 3-DZNeP partially attenuated the antifibrotic effects of emodin in both obstructed kidneys and NRK-49F cells.196 Additionally, Yang et al demonstrated that emodin alleviates renal fibrosis by modulating HGF and the TGF-β1/Smad signaling pathway.197 Ma et al reported that emodin mitigates renal fibrosis in rats by targeting the TGF-β1/Smad signaling pathway and suppressing Smad-specific E3 ubiquitin protein ligase 2 expression.145 Guan et al showed that a combination of rhein and Danshensu attenuates renal damage by inhibiting the TGF-β1/Smad3 pathway in 5/6 nephrectomized (NX) rats.198 These findings suggest that anthraquinones attenuate renal fibrosis by modulating the TGF-β1/Smad signaling pathway (Figure 2).
Regulation of Iƙb/NF-Ƙb Signalling Pathway by Anthraquinones
Using the 5/6 nephrectomized rat model, several studies have demonstrated that anthraquinones can inhibit renal fibrosis by targeting the IκB/NF-κB signaling pathway (Figure 3). For example, Liu et al reported that rhein protects against renal injury by reducing the expression of TNF-α, interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) via the NF-κB signaling pathway in 5/6 nephrectomized rats.137 Similarly, in vitro experiments revealed that rhein suppresses LPS-mediated NF-κB activation by inhibiting the phosphorylation of IκBα, blocking its nuclear translocation.137
In addition, Gu et al found that chrysophanol protects against TIF by suppressing the Naked cuticle 2/NF-κB pathway.199 Lu et al demonstrated that treatment with nanoparticle-mediated delivery of emodin via colonic irrigation reduces serum levels of IL-1β, IL-6, and LPS, improves intestinal barrier function, and downregulates the protein expression of TLR4, myeloid differentiation primary response protein 88 (MyD88), and NF-κB.151 Furthermore, 16S rDNA analysis indicated that nanoparticle-mediated emodin delivery effectively regulates microbiota disturbances in CKD.151 These findings suggest that anthraquinones mitigate renal fibrosis by reducing oxidative stress and inflammation by regulating the IκB/NF-κB signaling pathway (Figure 3).
Rhein Blunted CKD and Renal Fibrosis by Improving Klotho Expression
Klotho, a crucial anti-ageing protein, is highly expressed in the main tubular segments of healthy adult kidneys.200 However, Klotho expression is significantly reduced in ageing animals and humans. Zhang et al identified rhein as a potent Klotho upregulator, significantly preserving Klotho protein expression in UUO-induced TIF in mice.54 Further investigation revealed that Klotho loss in TIF is associated with promoter hypermethylation caused by aberrant expression of DNA methyltransferases (DNMT) 1 and 3a. Notably, the anti-TIF effects of rhein were abolished mainly in shRNA-Klotho-transfected cells, demonstrating the dependence of these effects on Klotho.54
The same research group further demonstrated that rhein significantly reverses renal Klotho deficiency in adenine-induced CKD in mice.201 Mechanistic studies revealed that rhein inhibits the induction of DNMT1 and DNMT3a, reducing Klotho promoter hypermethylation. However, Klotho knockdown partially abrogated the renoprotective effects of rhein.201 Additionally, Bi et al reported that Klotho preservation by rhein promotes TLR4 proteolysis and mitigates LPS-mediated AKI.202 These findings suggest that regulating Klotho expression by rhein contributes to its renoprotective effects, offering new insights into Klotho-targeted therapies for kidney disease.
Activation of SIRT/FOXO Signalling Pathway by Anthraquinones
Among the four FOXO transcription factors, FOXO1, FOXO3α, FOXO4, and FOXO6, FOXO3α plays a key role in regulating oxidative stress.203 Wu et al demonstrated that rhein inhibits TGF-β1-induced EMT and oxidative stress by activating the Sirtuin 3 (SIRT3)/forkhead box O3a (FOXO3α) signaling pathway, providing renoprotective effects in 5/6 nephrectomized-induced CKD.138 The antioxidant and antifibrotic functions of rhein are closely associated with increased FOXO3α nuclear translocation mediated by SIRT3 activation, highlighting the critical role of the SIRT3/FOXO3α signaling pathway in the renal protection conferred by rhein.138
As a SIRT1 agonist, resveratrol protects against oxidative stress by activating the SIRT1 signaling pathway, inhibiting ROS production,204 preventing NF-κB activation, and stimulating AMPK.205 Resveratrol treatment enhances SIRT1 deacetylase activity, reduces acetylated FOXO3α expression, and mitigates hyperglycemia-induced oxidative stress in vivo and in vitro.206 These findings suggest anthraquinones may attenuate renal fibrosis by modulating the SIRT/FOXO signaling pathway.
Regulation of AMPK and PI3K/Akt/mTOR Signalling Pathways by Anthraquinones
Excessive exogenous adenine induces metabolic abnormalities that mimic chronic renal insufficiency in humans. Tu et al reported that rhubarb inhibits autophagic activation and renal fibrosis in rats with adenine-induced renal tubular injury.207 Further studies revealed that rhein suppresses autophagy by regulating AMPK-dependent mTOR, extracellular signal-regulated kinase (ERK), and p38 MAPK signaling pathways207 (Figure 3). Similarly, Dou et al demonstrated that aloe-emodin attenuates TIF by inhibiting the PI3K/Akt/mTOR signaling pathway in the obstructed kidneys of UUO mice and TGF-β1-induced HK-2 cells153 (Figure 3).
Regulation of STAT3, Shh-GLI1 and HMGA2 Signalling Pathways by Anthraquinones
Several studies have shown that the beneficial effects of anthraquinones are associated with the STAT3, Sonic hedgehog-Glioma-associated oncogene 1 (Shh-GLI1), and high mobility group AT-hook 2 (HMGA2) signaling pathways. Recent evidence suggests that STAT3 is a critical pathway in the progression of CKD.208 Chen et al reported that rhein suppresses TIF by regulating the expression of phosphorylated STAT3, Bax, and Bcl-2.209
The Shh signaling pathway regulates renal development, patterning, and proliferation. GLI1-expressing cells are a primary source of activated fibroblasts in multiple organs. Luo et al demonstrated that rhein alleviates TIF by modulating the Shh-GLI1 signaling pathway.210 HMGA2 is implicated in TGF-β1-mediated EMT through various mechanisms. Wang et al showed that emodin mitigates renal injury and TIF by regulating the miR-490-3p/HMGA2 signaling pathway.211 These findings suggest that anthraquinones can attenuate renal fibrosis by targeting the STAT3, Shh-GLI1, and HMGA2 signaling pathways.
Conclusions
This review highlights the anthraquinones in R. officinale on treating AKI and CKD, emphasizing their underlying molecular mechanisms. Anthraquinones exert their effects by modulating key signaling pathways, including TGF-β1/Smad, IκB/NF-κB, Keap1/Nrf2, and Wnt/β-catenin, as well as through the regulation of apoptosis and autophagy. These mechanisms highlight the critical role of anthraquinones in providing anti-inflammatory, antioxidative, and anti-fibrotic effects. These pharmacological data provide evidence for treatment of AKI and CKD of R. officinale and present a concept-driven therapeutic strategy for renal disease management. However, most current studies are based on animal models or cell experiments, with limited clinical trials or real-world applications. Despite evidence of the broad renoprotective effects of R. officinale, certain limitations persist. These include poor solubility, low bioavailability, suboptimal intestinal absorption, long-term dose dependence for specific targets, and potential hepatotoxicity or nephrotoxicity. Thus, although R. officinale has significant promise, challenges remain in advancing its clinical applications, presenting opportunities and obstacles for future research and development.
Abbreviations
AKI, Acute kidney injury; ATP, adenosine triphosphate; α-SMA, alpha smooth muscle actin; AMPK, AMP-activated protein kinase; Bcl-2, B-cell lymphoma 2; Bax, B-cell lymphoma 2 associated X; CKD, chronic kidney disease; DKD, diabetic kidney disease; ER, endoplasmic reticulum; ESRD, end-stage renal disease; EMT, epithelial–mesenchymal transition; EMC, extracellular matrix; FOXO, Forkhead box O; GSK-3β, glycogen synthase kinase-3 beta; HG, high glucose; HMGA2, high mobility group AT-hook 2; H/R, hypoxia-reoxygenation; IgAN, immunoglobulin A nephropathy; IƙB, inhibitor of kappa B; IRF4, interferon regulatory factor 4; IRI, ischemia-reperfusion injury; Keap1, kelch-like ECH-associated protein 1; LPS, lipopolysaccharide; mTOR, mammalian target of rapamycin; NOX1, nicotinamide adenine dinucleotide phosphate oxidase 1; Nrf2, nuclear factor erythroid 2-related factor 2; NF-ƙB, nuclear factor kappa B; PPARγ, peroxisome proliferator-activated receptor gamma; PI3K, phosphoinositide 3-kinases; Akt, protein kinase B; PKC, protein kinase C; Rac1, Ras-related C3 Botulinum toxin substrate 1; ROS, reactive oxygen species; Rhein-8-O-Glc, rhein-8-O-β-D-glucopyranoside; STAT3, signal transducer and activator of transcription 3; SIRT1, Sirtuin 1; Smad, small mothers against decapentaplegic; Shh-GLI1, sonic hedgehog-glioma-associated oncogene 1; STZ, streptozotocin; TLR, toll-like receptors; TCM, traditional Chinese medicine; TGF-β1, transforming growth factor beta1; TIF, tubulointerstitial fibrosis; TNF-α, tumor necrosis factor alpha; UUO, unilateral ureteral obstruction.
Funding
This study was supported by the Shaanxi Key Science and Technology Plan Project (No. 2023-ZDLSF-26) and National Natural Science Foundation of China (Nos. 82274079, 82274192, and 82074002).
Disclosure
Hao-Yu Feng and Yi-Qi Wang are co-first authors for this study. The authors declare that they have no conflicts of interest in this work.
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