Effects of Rhein on the Kidney

Effects of Rhein on the Kidney: Comparison

Please note this is a comparison between Version 3 by Yanna Zhu and Version 2 by Yanna Zhu.

Rhein is a monomeric component of anthraquinone isolated from rhubarb, a traditional Chinese medicine. It has anti-inflflammation, anti-oxidation, anti-apoptosis, anti-bacterial and other pharmacological activities, as well as a renal protective effects. Rhein exerts its nephroprotective effects mainly through decreasing hypoglycemic and hypolipidemic, playing anti-inflflammatory, antioxidant and anti-fifibrotic effects and regulating drug-transporters. However, the latest studies show that rhein also has potential kidney toxicity in case of large dosages and long use times. The present review highlights rhein’s molecular targets and its different effects on the kidney based on the available literature and clarififies that rhein regulates the function of the kidney in a positive and negative way. It will be helpful to conduct further studies on how to make full use of rhein in the kidney and to avoid kidney damage so as to make it an effective kidney protection drug.

traditional Chinese medicine
rhein
kidney protection
nephrotoxicity

1. Introduction

Rhein (molecular formula C₁₅H₈O₆), a lipophilic anthraquinone, is the main component of Senna alexandrina Mill., Rheum palmatum L., Aloe barbadensis Miller, and Polygonum multiflorum Thunb [17]. It contains two hydroxyl groups and one carboxyl group and has strong polarity and electrochemical REDOX properties [18]. Rhein has a lot of pharmacological effects, such as anti-inflammation [19], anti-cancer [20], anti-fibrosis [21], antioxidation [22], hepatoprotective [23], nephroprotective [24], lipid-lowering [25], and antimicrobial activities [26]. In spite of this, its poor solubility and low bioavailability limit its clinical applications. The study of rhein and its derivatives has been enriched by advances in drug separation and synthesis. Diacerein is one of the most common and representative derivatives of rhein, and it is used for the treatment of arthritis owing to its ability in reducing osteoclast formation and inhibiting the synthesis of resorptive factors [27]. Additionally, nanodrug delivery systems have been designed to overcome the poor solubility of rhein [28]. The pharmacological effects of these compounds lay the groundwork for the treatment of liver disease, osteoarthritis, diabetes, atherosclerosis, and a variety of cancers [29,30,31,32,33]. However, it has recently been reported that rhein also causes hepatotoxicity and nephrotoxicity [22,34].

2. Nephroprotective Effect

The pharmacological benefits of rhein for human health are increasingly recognized. Rhein, and its derivatives, analogs, and compound preparations show the nephroprotective activities against various kidney disease, especially diabetic nephropathy (DN) and drug-induced AKI. One of the most common microvascular complications of diabetes is DN [35], which is a leading cause of CKD and end-stage renal disease (ESRD) worldwide [36]. The pathophysiology of DN is quite complex with two main initiating factors: abnormal metabolism and hemodynamic activity [37]. Pathogenesis of DN includes metabolic dysregulation, inflammation, oxidative stress, abnormal cytokines, etc., [38]. Considering multiple pathogenic mechanisms, we therefore need to develop drugs with multiple targets to treat DN effectively. The pathogenesis of AKI may be related to the specific injury of renal vessels, glomeruli, renal tubules, or interstitial compartments [2]. AKI can cause apoptosis, autophagy, and regulated and genetically controlled cell death as a result of cell damage [39]. Rhein has a variety of therapeutic targets as a TCM ingredient (or element), and its protective effect on the above targets has been gradually examined. Rhein is highly effective for the treatment of kidney-related diseases among natural components. The schematic mechanism of the signal pathway of the nephroprotective effects of rhein is shown in Figure 1.

Figure 1. Signal pathway of the nephropropective effects of rhein.

2.1. Hypoglycemic and Hypolipidemic Proprieties of Rhein

Some studies have shown that the mitochondrial event chain caused by hyperglycemia may be one of the pathogeneses of diabetic nephropathy [78]. Rhein treatment showed significant improvements in glucose-dependent and independent insulin secretion in db/db mice by preserving β-cell mass and inhibiting apoptosis [45]. Another study [47] showed that rhein protects pancreatic cells from apoptosis by inhibiting the expression of dynamin-related protein 1 (Drp1). It may be possible to prevent or treat diabetes by rhein in the near future. Rhein has been shown to improve insulin resistance and renal injury in rats and db/db mice [79]. Furthermore, rhein and benazepril were evaluated individually and in combination in diabetic mice. Benazepril and rhein showed similar kidney protection [40]. In db/db mice, a combined application had a better kidney protection effect [40]. This reduced urinary albumin excretion, decreased plasma glucose, cholesterol, relieved glomerular hypertrophy, mesangial expansion and proliferation, and inhibited the expression of fibronectin (FN) and transforming growth factor- β1 (TGF-β1) [40]. In order to elucidate the therapeutic mechanism of rhein on DN, Zheng J et al. (2008) examined the effect of rhein on the hexosamine pathway [41]. Due to its role as a nutrient sensor, the hexosamine pathway has been associated with metabolic disorders and cellular hypertrophy when glucose levels are high [80]. The hexosamine pathway is one of the mechanisms responsible for renal damage in diabetes. To mimic mesangial cells under diabetic conditions, transgenic mesangial cell lines (MCGT1) overexpressing glucose transporter 1 (GLUT1) were used. GLUT1, an integral membrane protein, transports glucose into mesangial cells via glucose gradients [81].

2.2. Anti-Inflammatory Proprieties of Rhein

As a result of hyperglycemia, advanced glycation end products (AGEs) damage the vascular endothelium, glomeruli, and tubules, which facilitates the emergence of DN eventually [85]. Diabetes is an entity of inflammation because its pathogenesis involves multiple inflammatory/proinflammatory factors, and it is characterized by chronic low-grade inflammatory disease [86]. The model of early diabetic nephropathy was established and showed increases in serum microalbuminuria, NADPH oxidase expression, and PKR-like eukaryotic initiation factor 2α kinase (PERK) level, and a decrease in connexin 43 (Cx43) in renal tissue. Upregulation of nuclear transcription factors, such as PERK, reveals the presence of endoplasmic reticulum stress (ER stress) [87]. Cx43, a family of connexins, may play a key role in exchanging small molecules within glomeruli and tubules in the kidney, which is essential for normal renal function [43]. Argirein, a derivative of rhein, can be produced by combining rhein with L-arginine by forming a hydrogen bond. It has anti-inflammatory activity derived from rhein. Argirein (200, 100, and 50 mg/kg) is more effective than aminoguanidine (AMG) (100 mg/kg), which has anti-inflammatory activity as a positive reference agent in reversing the above changes [43]. The mortality rate of AKI is about 70–80 % [95,96]. Currently, renal replacement therapy (RRT) is the only effective treatment for AKI [97]. Inflammatory response inherent to sepsis is thought to be the direct mechanism of AKI [98]. Based on rhein’s anti-inflammatory pharmacological activity, Yu C et al. (2015) explored the effects of rhein on sepsis-induced AKI by using lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) models [55]. The potential mechanism of rhein may be related to its anti-inflammatory effects. Rhein inhibited the activation of NF-κB via restraining the expression and phosphorylation of the relevant proteins in the NF-κB signal pathway and hindering the transcription of NF-κB p65 [55]. It brings a new research direction for solving AKI related to endotoxemia. At the same time, the research of Liu M et al. (2021) also confirms this point [73]. The 5/6 nephrectomy model (5/6 Nx) in rats and LPS-induced HK-2 cells were used in this study, and the results indicated that rhein inhibits inflammatory signaling pathways via decreasing the production of TNF-α, IL-6, and monocyte chemotactic protein (MCP-1) [73]. In addition, by inhibiting NF-κB phosphorylation, rhein diminished LPS-induced NF-κB activation [73]. The above results clearly indicate that rhein can be a promising therapeutic agent for renal disease by inhibiting multiple inflammatory mediators [55,73].

2.3. Antioxidant Proprieties of Rhein

Rhein attenuated APAP-induced hepatotoxicity and nephrotoxicity in a dose-dependent manner [23]. The levels of serum glutamate-pyruvate transaminase (GPT), glutamate-oxaloacetic transaminase (GOT), urea nitrogen (UREA), creatinine (Crea), and reactive oxygen species (ROS) production were significantly decreased, and the contents of nitric oxide (NO), MDA, and GSH were recovered in the rhein treatment group [23]. Rhein relieved APAP-induced liver and kidney injury by ameliorating oxidative stress [23]. Diacerein (DIA) is used to treat osteoarthritis. DIA enters the body and is rapidly converted into its active metabolite rhein [63]. Furthermore, studies have been conducted one after another on whether DIA can alleviate AKI. The antioxidant effects of DIA were reported to protect renal function against doxorubicin-induced AKI [63].

2.4. Antifibrotic Proprieties of Rhein

CKD and chronic kidney failure (CRF) develop as a result of renal fibrosis. The pathological mechanism of renal fibrosis is relatively complex. There is a variety of stimulating factors or mediators, such as growth factors, cytokines and toxins, which induce the occurrence of fibrosis through a variety of mechanisms and signal pathways [113,114]. TGF-β has been proven to be a major pathogenic factor for the progressive development of renal fibrosis [115]. TGF-β can induce renal tubular epithelial cells to transform into renal mesenchymal fibroblasts through the epithelial–mesenchymal transition (EMT) process [116]. In addition to the TGF-β pathway, the Notch, Wnt, and Hedgehog signaling pathways can also be activated in response to renal injury, thereby promoting renal fibrosis [117]. TGF-β regulates renal fibrosis progression through classic and non-classic pathways. The classical TGF-β pathway includes two signaling pathways, namely TGF-β/Smad and bone morphogenetic protein (BMP) [115]. However, they have opposite effects although they have similar downstream Smad signaling pathways. Smad3 is a key downstream mediator of TGF-β signal transduction [115]. BMP7 is a member of the TGF-β superfamily that antagonizes the effects of TGF-β [118]. Like liver growth factor (HGF), they both have anti-fibrotic effects [118]. Combined therapy of rhein and Danshensu (DSS) had a certain renal protective effect on chronic kidney damage. The mechanism may be related to anti-inflammatory and anti-fibrosis by downregulating the NF-κB-related pathway and inhibiting the TGF-β/Smad3 pathway, respectively [56]. Other studies have shown that rhein improved renal function and reduced renal fibrosis and interstitial inflammation by inducing HGF and BMP7 production [50]. In addition to the classical Smad signaling pathway, TGF-β can also regulate the downstream cellular response through other non-classical pathways and then adjust the pathological process of renal fibrosis [115]. p38 mitogen-activated protein kinase (MAPK) is one of the atypical signaling pathways of TGF-β1. TGF-β1 activates the downstream signaling pathway MKK3-p38 MAPK cascade through the activation of TAK1, ultimately leading to cell fibrosis [119]. Rhubarb and Astragalus capsules (RAC) that contain 2.25 mg/g rhein have been used in a clinical treatment for chronic kidney disease [70].

2.5. Benefits of Rhein Via Drug-Transporter

Renal transporters transport endogenous substances, poisons, and drugs from the blood to the urine. As a result of renal injury, uptake transporters and efflux transporters are altered, which affects toxic excretion and aggravates renal injury [133]. Previous research by our group has shown that the expressions of organic anion transporter 1 (OAT1), OAT3, and multidrug resistance related protein 2 (MRP2) were significantly decreased after cisplatin-induced AKI, which reduced the excretion of endotoxin and aggravated renal injury [133]. There are few studies on the relationship between the various pharmacological effects of rhein and transporters. Zhu Y et al. (2022) [24] showed that the gene levels and protein expressions of the renal transporters including Oat1, Oat3, Organic cation transporter 2 (OCT2), mammal multidrug, and toxin extrusion proteins 1 (Mate 1), Mrp2, and P-glycoprotein (P-gp) in vancomycin-induced nephrotoxicity (VIN) were significantly decreased. Plasma creatinine, BUN, and plasma indoxyl sulfate were not excreted efficiently. Rhein reversed the expressions of the above transporters, and thereby promoted the excretion of endotoxins and finally alleviated renal injury [24]. The discovery of VIN’s pathogenesis expands the field of study on the kidney protection effects of VIN.

3. Toxicological Effects in Kidney

Total rhubarb anthraquinones (TRAs) include emodin, rhein, chrysophanol, aloe emodin, and other substances [134]. However, the clinical cases of liver injury and the progression of kidney disease caused by TCM contained TRAs are increasing. Rhein is an important ingredient in TRAs, which affects the kidneys in a positive and negative way. Studies on the nephrotoxicity effects of rhein and the related mechanisms are shown in Figure 2.

Figure 2. Signal pathway of nephrotoxic effect of rhein.

3.1. Rhein Nephrotoxicity: Mechanisms of Action and Possible Causes

Through the literature review, the difference between the kidney protection and nephrotoxicity effects of rhein may be related to the dosage and duration of rhein. When rhein exerted kidney protection effects, the dosage of rhein in animal experiments was mostly 20 to 150 mg/kg/day, and the duration of administration was mostly less than 14 days, with the longest time being 8 weeks when the rhein was at a slightly lower dosage. In mice, HU Y et al. (2019) observed renal toxicity after long-term administration of rhein [139]. Mice were randomly divided into three groups: blank group, low-dose rhein group (0.175g/kg) and high-dose rhein group (0.35g/kg). The drug was administered by gavage for 60 days [139]. Compared to the blank group of the same sex, BUN and SCr of mice in the administration group were increased, and the body weight of mice in the rhein high-dose group decreased [139]. The renal index of male mice in the administration group decreased significantly, and the content of GSH-Px decreased and the expression of TGF-β1 increased in male mice in the rhein high-dose group [139]. Its potential toxic mechanism may be caused by the imbalance of glutathione antioxidant system that can induce excessive oxidation, inflammatory reaction, and the apoptosis induced by the activation of caspase-3 [139].

In cell experiments, the transition between kidney protection and nephrotoxicity is more closely related to dose and duration of administration. Da H et al., (2009) evaluated the cytotoxic effects of emodin and rhein in HK-2 cells [135]. The results showed that both emodin and rhein could inhibit the growth of HK-2 cells, but the inhibitory effect of rhein was weaker than that of emodin [135]. From the experimental results of rhein on the survival rate of HK-2 cells, we found that rhein had obvious inhibitory effect on cell proliferation when it was treated with 40 μM for 24 hours, and the inhibitory effect gradually increased with the extension of incubation time; while the cell proliferation could be significantly inhibited after 12 hours of administration when the dosage of rhein was 100 μM [135]. It was preliminarily elucidated that rhein caused renal injury by inducing apoptosis. Researchers have also carried out a series of studies to further clarify the nephrotoxicity mechanisms of rhein. Most studies have shown that it is related to the induction of apoptosis (Figure 32). In addition to death receptor signaling, mitochondrial death pathway, oxidative stress, and endoplasmic reticulum stress all contribute to apoptosis [140]. It was found that rhein directly inhibited HK-2 cells growth and increased the apoptosis in a dose- and time-dependent manner according to the study of Yang J et al., (2015) [136]. Rhein (50 and 100 μM, 24 hours after administration) increased the mRNA levels of amino terminal kinase (c-Jun), activated transcription factor-2 (ATF-2) and caspase-3, and upregulated the expression of p38 MAPK, cleaved caspase-3. These results suggest that rhein may induce apoptosis of HK-2 cells through MAPK signaling pathway [136]. Hao S et al., (2015) [137] also found rhein could dose-dependently inhibit the viability of HK-2 cells, increase the release of lactate dehydrogenase (LDH) and apoptosis rate, and significantly up-regulate the mRNA or protein expressions of Fas, FasL, FADD, caspase-3, caspase-8 and Cytochrome C (Cyt-c). Apoptosis induced by Fas pathway may be the mechanism of rhein's toxic effects on HK-2 cells in vitro. In another study [138], rhein reduced mitochondrial membrane potential and intracellular ATP level, released Cyt-c, and decreased Bcl-2 and Bax protein levels in HK-2 cells. Meanwhile, rhein increased intracellular ROS level and inhibited mitochondrial uncoupling protein 2 (UCP2) expression, which regulates mitochondrial membrane potential, ROS generation and ATP synthesis [138]. Rhein inhibited the expression of UCP2, significantly enhanced the oxidative stress in cells, and thus promoted cell apoptosis, indicating the potential role of UCP2 in rhein nephrotoxicity [138].

3.2. Methods for controlling rhein toxicity

In order to use rhein reasonably and safely, there may be some measures we should take. On the one hand, it is important to control the dosage and duration of rhein administration as described above; on the other hand, the compatibility of TCM can enhance its protective effects and reduce the toxicity. For instance, different doses of astragaloside IV (10, 20 and 40 μM) could reduce the occurrence of rhein-induced vacuolation, cell fusion, and the increase of necrotic cells in HK-2 cells [141]. After the combination of rhein and astragaloside IV in HK-2 cells for 48 hours, the cell inhibition rate and LDH leakage rate were significantly reduced [141]. The compatibility significantly increased the contents of SOD and GSH in cells and down-regulated the expression of MDA, which indicates that astragaloside IV could significantly inhibit the oxidative stress injury caused by rhein and then protect cells [141].

Conclusion and Future Prospects

This review comprehensively summarizes the research progress and molecular targets of rhein in positive and negative regulatory effects on the kidney. In most cases, rhein is shown to have a protective effect on the kidneys. At present, there are limited studies on the nephrotoxicity of rhein, and most of them are in vitro cell experiments. But the data still shows that the difference between kidney protection and nephrotoxicity of rhein may be related to the dosage and duration of rhein. More in vitro and in vivo experiments of the nephrotoxicity of rhein are needed for further investigation. This review summarizes all the existing literature and the specific mechanisms on the positive and negative regulatory effects of rhein on the kidney, which is convenient for basic researchers to better and faster refer to relevant references and provide convenience for further research. It is hoped that the nephroprotective effect of rhein can be fully exerted and its nephrotoxicity can be avoided through the joint efforts of researchers.

Abbreviations

AP allopurinol; APAP acetaminophen; APS astragalus polysaccharide; α-SMA α-smooth muscle actin; BMP-7 bone morphogenic protein 7; BSA bovine serum albumin; CAN chronic allograft nephropathy; CCl4 carbon tetrachloride; db/db diabetic obese; Cox2 cytochrome oxidase subunit 2; DFD Dahuang Fuzi Decoction; DNMTs DNA methyltransferases; Dox doxorubicin; EMT epithelial-mesenchymal transition; FN fibronectin; GFAT glutamine fructose 6-phosphate aminotransferase; GSK3b glycogen synthase kinase 3 beta; HEK human embryonic kidney; HGF hepatocyte growth factor; HK-2 Human Kidney-2; IgAN IgA nephropathy; IL-1 interleukin 1; ILK integrin-linked kinase; JNK c-JunNH2-terminal kinase; lncRNAs long noncoding RNAs; LPS lipopolysaccharide; MAPK mitogen-activated protein kinase; MMP-9 matrix metalloproteinase-9; MCGT1 mesangial cells were

transinfected with the human GLUT1 gene; MCLacZ mesangial cells transinfected with bacterial β-galactosidase; NF-κB nuclear factor kappa-B; Nrf2 the nuclear factor E2-related factor 2; NRK-49F normal Rat Kidney-49F; Nx nephrectomied; p38-MAPK p38 mitogen-activated protein kinase; PPARα peroxisome proliferator-activated receptor-α; RAC Rhubarb and astragalus capsule; RHL rhein lysinate; SAM senescence-accelerated mouse; SAMR1 senescence-resistant inbred strain 1; SAMP10 senescence-prone inbred strain 10; SD Sprague–Dawley; SIRT1 Sirtuin-1; STZ streptozotocin; TCMK-1 transformed C3H mouse kidney-1; TGF-β1 transforming growth factor-β1; TIMP1 TIMP metallopeptidase inhibitor 1; TLR4 toll like receptor 4; TNF tumor necrosis factor; UUO unilateral ureteral obstruction; VCM vancomycin

Funding: National Natural Science Foundation of China, Grant/Award Number: 82003837

References

Tienda-Vázquez, M.A.; Morreeuw, Z.P.; Sosa-Hernández, J.E.; Cardador-Martínez, A.; Sabath, E.; Melchor-Martínez, E.M.; Iqbal,

H.M.N.; Parra-Saldívar, R. Nephroprotective Plants: A Review on the Use in Pre-Renal and Post-Renal Diseases. Plants 2022,

11, 818. [CrossRef] [PubMed]

Radi, Z.A. Kidney Pathophysiology, Toxicology, and Drug-Induced Injury in Drug Development. Int. J. Toxicol. 2019, 38, 215–227.

[CrossRef] [PubMed]

Luyckx, V.A.; Tonelli, M.; Stanifer, J.W. The global burden of kidney disease and the sustainable development goals. Bull. World

Health Organ. 2018, 96, 414. [CrossRef] [PubMed]

Hansrivijit, P.; Gadhiya, K.P.; Gangireddy, M.; Goldman, J.D. Risk Factors, Clinical Characteristics, and Prognosis of Acute Kidney

Injury in Hospitalized COVID-19 Patients: A Retrospective Cohort Study. Medicines 2021, 8, 4. [CrossRef] [PubMed]

Konda, V.R.; Arunachalam, R.; Eerike, M.; Rao, K.R.; Radhakrishnan, A.K.; Raghuraman, L.P.; Meti, V.; Devi, S. Nephroprotective

effect of ethanolic extract of Azima tetracantha root in glycerol induced acute renal failure in Wistar albino rats. J. Tradit.

Complementary Med. 2016, 6, 347–354. [CrossRef] [PubMed]

Perazella, M.A. Pharmacology behind Common Drug Nephrotoxicities. Clin. J. Am. Soc. Nephrol. CJASN 2018, 13, 1897–1908.

[CrossRef] [PubMed]

Chen, T.K.; Knicely, D.H.; Grams, M.E. Chronic Kidney Disease Diagnosis and Management: A Review. JAMA 2019, 322, 1294–1304.

[CrossRef]

Jha, V.; Garcia-Garcia, G.; Iseki, K.; Li, Z.; Naicker, S.; Plattner, B.; Saran, R.; Wang, A.Y.; Yang, C.W. Chronic kidney disease:

Global dimension and perspectives. Lancet 2013, 382, 260–272. [CrossRef]

Yang, B.; Xie, Y.; Guo, M.; Rosner, M.H.; Yang, H.; Ronco, C. Nephrotoxicity and Chinese Herbal Medicine. Clin. J. Am. Soc.

Nephrol. CJASN 2018, 13, 1605–1611. [CrossRef]

Naik, R.P.; Derebail, V.K.; Grams, M.E.; Franceschini, N.; Auer, P.L.; Peloso, G.M.; Young, B.A.; Lettre, G.; Peralta, C.A.; Katz, R.;

et al. Association of sickle cell trait with chronic kidney disease and albuminuria in African Americans. JAMA 2014, 312, 2115–2125.

[CrossRef]

Inker, L.A.; Astor, B.C.; Fox, C.H.; Isakova, T.; Lash, J.P.; Peralta, C.A.; Kurella Tamura, M.; Feldman, H.I. KDOQI US commentary

on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am. J. Kidney Dis. Off. J. Natl. Kidney

Found. 2014, 63, 713–735. [CrossRef]

Jager, K.J.; Kovesdy, C.; Langham, R.; Rosenberg, M.; Jha, V.; Zoccali, C. A single number for advocacy and communication

worldwide more than 850 million individuals have kidney diseases. Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl.

Assoc.–Eur. Renal Assoc. 2019, 34, 1803–1805. [CrossRef]

Capolongo, G.; Capasso, G.; Viggiano, D. A Shared Nephroprotective Mechanism for Renin-Angiotensin-System Inhibitors,

Sodium-Glucose Co-Transporter 2 Inhibitors, and Vasopressin Receptor Antagonists: Immunology Meets Hemodynamics. Int. J.

Mol. Sci. 2022, 23, 3915. [CrossRef]

Blair, H.A. Tolvaptan: A Review in Autosomal Dominant Polycystic Kidney Disease. Drugs 2019, 79, 303–313. [CrossRef]Molecules 2022, 27, 6572

16 of 20

Perkovic, V.; Jardine, M.J.; Neal, B.; Bompoint, S.; Heerspink, H.J.L.; Charytan, D.M.; Edwards, R.; Agarwal, R.; Bakris, G.; Bull,

S.; et al. Canagliflflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N. Engl. J. Med. 2019, 380, 2295–2306. [CrossRef]

Basist, P.; Parveen, B.; Zahiruddin, S.; Gautam, G.; Parveen, R.; Khan, M.A.; Krishnan, A.; Shahid, M.; Ahmad, S. Potential

nephroprotective phytochemicals: Mechanism and future prospects. J. Ethnopharmacol. 2022, 283, 114743. [CrossRef]

Ge, J.H.; Liu, X.H.; Xu, H.; Xu, D.Y.; Bai, F.P. Identifification of different varieties of Rhei Radix et Rhizoma based on chemical

analysis. China J. Chin. Mater. Med. 2015, 40, 2309–2313.

Li, X.H.; Li, M.; Tao, Y.R. Development of pharmacological effects of rhein and its derivatives. Drugs Clinic. 2010, 25, 417–421.

Hu, J.; Wang, D.; Wu, H.; Yang, Z.; Yang, N.; Dong, J. Long non-coding RNA ANRIL-mediated inflflammation response is involved

in protective effect of rhein in uric acid nephropathy rats. Cell Biosci. 2019, 9, 11. [CrossRef]

Henamayee, S.; Banik, K.; Sailo, B.L.; Shabnam, B.; Harsha, C.; Srilakshmi, S.; Vgm, N.; Baek, S.H.; Ahn, K.S.; Kunnumakkara, A.B.

Therapeutic Emergence of Rhein as a Potential Anticancer Drug: A Review of Its Molecular Targets and Anticancer Properties.

Molecules 2020, 25, 2278. [CrossRef]

Chen, Y.; Mu, L.; Xing, L.; Li, S.; Fu, S. Rhein alleviates renal interstitial fifibrosis by inhibiting tubular cell apoptosis in rats. Biol.

Res. 2019, 52, 50. [CrossRef]

Zhou, Y.X.; Xia, W.; Yue, W.; Peng, C.; Rahman, K.; Zhang, H. Rhein: A Review of Pharmacological Activities. Evid.-Based

Complementary Altern. Med. eCAM 2015, 2015, 578107. [CrossRef]

Zhao, Y.L.; Zhou, G.D.; Yang, H.B.; Wang, J.B.; Shan, L.M.; Li, R.S.; Xiao, X.H. Rhein protects against acetaminophen-induced

hepatic and renal toxicity. Food Chem. Toxicol. 2011, 49, 1705–1710. [CrossRef]

Zhu, Y.; Jin, H.; Huo, X.; Meng, Q.; Wang, C.; Sun, P.; Ma, X.; Sun, H.; Dong, D.; Wu, J.; et al. Protective effect of Rhein against

vancomycin-induced nephrotoxicity through regulating renal transporters and Nrf2 pathway. Phytother. Res. PTR 2022, 1–19.

[CrossRef]

Sheng, X.; Wang, M.; Lu, M.; Xi, B.; Sheng, H.; Zang, Y.Q. Rhein ameliorates fatty liver disease through negative energy balance,

hepatic lipogenic regulation, and immunomodulation in diet-induced obese mice. Am. J. Physiol. Endocrinol. Metab. 2011,

300, E886–E893. [CrossRef]

Nguyen, A.T.; Kim, K.Y. Rhein inhibits the growth of Propionibacterium acnes by blocking NADH dehydrogenase-2 activity. J.

Med. Microbiol. 2020, 69, 689–696. [CrossRef]

Boileau, C.; Tat, S.K.; Pelletier, J.P.; Cheng, S.; Martel-Pelletier, J. Diacerein inhibits the synthesis of resorptive enzymes and

reduces osteoclastic differentiation/survival in osteoarthritic subchondral bone: A possible mechanism for a protective effect

against subchondral bone remodelling. Arthritis Res. Ther. 2008, 10, R71. [CrossRef]

Wang, G.; Li, Q.; Chen, D.; Wu, B.; Wu, Y.; Tong, W.; Huang, P. Kidney-targeted rhein-loaded liponanoparticles for diabetic

nephropathy therapy via size control and enhancement of renal cellular uptake. Theranostics 2019, 9, 6191–6208. [CrossRef]

[PubMed]

Guo, M.Z.; Li, X.S.; Shen, D.M.; Guan, X.Q.; Xu, H.R.; Gao, J. Effect of Rhein on the development of hepatic fifibrosis in rats. Chin. J.

Hepatol. 2003, 11, 26–29.

Moldovan, F.; Pelletier, J.P.; Jolicoeur, F.C.; Cloutier, J.M.; Martel-Pelletier, J. Diacerhein and rhein reduce the ICE-induced IL-1beta

and IL-18 activation in human osteoarthritic cartilage. Osteoarthr. Cartil. 2000, 8, 186–196. [CrossRef]

Heo, S.K.; Yun, H.J.; Park, W.H.; Park, S.D. Rhein inhibits TNF-alpha-induced human aortic smooth muscle cell proliferation via

mitochondrial-dependent apoptosis. J. Vasc. Res. 2009, 46, 375–386. [CrossRef] [PubMed]

Du, H.; Shao, J.Q.; Gu, P.; Wang, J.; Liu, Z.H. Effect of early intervention with rhein on islet function in db/db mice. J. South. Med.

Univ. 2011, 31, 1526–1529.

Chen, Y.Y.; Chiang, S.Y.; Lin, J.G.; Ma, Y.S.; Liao, C.L.; Weng, S.W.; Lai, T.Y.; Chung, J.G. Emodin, aloe-emodin and rhein inhibit

migration and invasion in human tongue cancer SCC-4 cells through the inhibition of gene expression of matrix metalloproteinase-9.

Int. J. Oncol. 2010, 36, 1113–1120. [CrossRef] [PubMed]

Sun, H.; Luo, G.; Chen, D.; Xiang, Z. A Comprehensive and System Review for the Pharmacological Mechanism of Action of

Rhein, an Active Anthraquinone Ingredient. Front. Pharmacol. 2016, 7, 247. [CrossRef]

Brown, W.V. Microvascular complications of diabetes mellitus: Renal protection accompanies cardiovascular protection. Am. J.

Cardiol. 2008, 102, 10l–13l. [CrossRef]

Skyler, J.S. Microvascular complications. Retinopathy and nephropathy. Endocrinol. Metab. Clin. N. Am. 2001, 30, 833–856.

[CrossRef]

Leon, C.A.; Raij, L. Interaction of haemodynamic and metabolic pathways in the genesis of diabetic nephropathy. J. Hypertens.

2005, 23, 1931–1937. [CrossRef]

Reidy, K.; Kang, H.M.; Hostetter, T.; Susztak, K. Molecular mechanisms of diabetic kidney disease. J. Clin. Investig. 2014,

124, 2333–2340. [CrossRef]

Radi, Z.A.; Stewart, Z.S.; O’Neil, S.P. Accidental and Programmed Cell Death in Investigative and Toxicologic Pathology. Curr.

Protoc. Toxicol. 2018, 76, e51. [CrossRef]

Jia, Z.H.; Liu, Z.H.; Zheng, J.M.; Zeng, C.H.; Li, L.S. Combined therapy of rhein and benazepril on the treatment of diabetic

nephropathy in db/db mice. Exp. Clin. Endocrinol. Diabetes 2007, 115, 571–576. [CrossRef]

Zheng, J.M.; Zhu, J.M.; Li, L.S.; Liu, Z.H. Rhein reverses the diabetic phenotype of mesangial cells over-expressing the glucose

transporter (GLUT1) by inhibiting the hexosamine pathway. Br. J. Pharmacol. 2008, 153, 1456–1464. [CrossRef]Molecules 2022, 27, 6572

17 of 20

Gao, Q.; Qin, W.S.; Jia, Z.H.; Zheng, J.M.; Zeng, C.H.; Li, L.S.; Liu, Z.H. Rhein improves renal lesion and ameliorates dyslipidemia

in db/db mice with diabetic nephropathy. Planta Med. 2010, 76, 27–33. [CrossRef]

Hu, C.; Cong, X.D.; Dai, D.Z.; Zhang, Y.; Zhang, G.L.; Dai, Y. Argirein alleviates diabetic nephropathy through attenuating

NADPH oxidase, Cx43, and PERK in renal tissue. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2011, 383, 309–319. [CrossRef]

He, D.; Lee, L.; Yang, J.; Wang, X. Preventive effects and mechanisms of rhein on renal interstitial fifibrosis in obstructive

nephropathy. Biol. Pharm. Bull. 2011, 34, 1219–1226. [CrossRef]

Du, H.; Shao, J.; Gu, P.; Lu, B.; Ye, X.; Liu, Z. Improvement of glucose tolerance by rhein with restored early-phase insulin secretion

in db/db mice. J. Endocrinol. Investig. 2012, 35, 607–612. [CrossRef]

Peng, L.; Yang, J.; Ning, C.; Zhang, J.; Xiao, X.; He, D.; Wang, X.; Li, Z.; Fu, S.; Ning, J. Rhein inhibits integrin-linked kinase

expression and regulates matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio in high glucose-induced

epithelial-mesenchymal transition of renal tubular cell. Biol. Pharm. Bull. 2012, 35, 1676–1685. [CrossRef]

Liu, J.; Chen, Z.; Zhang, Y.; Zhang, M.; Zhu, X.; Fan, Y.; Shi, S.; Zen, K.; Liu, Z. Rhein protects pancreatic β-cells from

dynamin-related protein-1-mediated mitochondrial fifission and cell apoptosis under hyperglycemia. Diabetes 2013, 62, 3927–3935.

[CrossRef]

Hu, G.; Liu, J.; Zhen, Y.Z.; Xu, R.; Qiao, Y.; Wei, J.; Tu, P.; Lin, Y.J. Rhein lysinate increases the median survival time of SAMP10

mice: Protective role in the kidney. Acta Pharmacol. Sinica 2013, 34, 515–521. [CrossRef]

Sheng-Nan, P.; Hui-Hong, Z.; Ai-Xiang, F.; Xiao-Wen, C.; Qing-Xian, Z. Protection of rhein on IgA nephropathy mediated by

inhibition of fifibronectin expression in rats. Indian J. Pharmacol. 2013, 45, 174–179. [CrossRef]

Su, J.; Yin, L.P.; Zhang, X.; Li, B.B.; Liu, L.; Li, H. Chronic allograft nephropathy in rats is improved by the intervention of rhein.

Transplant. Proc. 2013, 45, 2546–2552. [CrossRef]

Lian, Y.; Xie, L.; Chen, M.; Chen, L. Effects of an astragalus polysaccharide and rhein combination on apoptosis in rats with

chronic renal failure. Evid.-Based Complementary Altern. Med. eCAM 2014, 2014, 271862. [CrossRef] [PubMed]

Tu, Y.; Sun, W.; Wan, Y.G.; Gao, K.; Liu, H.; Yu, B.Y.; Hu, H.; Huang, Y.R. Dahuang Fuzi Decoction ameliorates tubular epithelial

apoptosis and renal damage via inhibiting TGF-β1-JNK signaling pathway activation in vivo. J. Ethnopharmacol. 2014, 156, 115–124.

[CrossRef] [PubMed]

Chen, X.; Peng, S.; Zeng, H.; Fu, A.; Zhu, Q. Toll-like receptor 4 is involved in a protective effect of rhein on immunoglobulin A

nephropathy. Indian J. Pharmacol. 2015, 47, 27–33. [CrossRef] [PubMed]

Baker, C.C.; Chaudry, I.H.; Gaines, H.O.; Baue, A.E. Evaluation of factors affecting mortality rate after sepsis in a murine cecal

ligation and puncture model. Surgery 1983, 94, 331–335. [PubMed]

Yu, C.; Qi, D.; Sun, J.F.; Li, P.; Fan, H.Y. Rhein prevents endotoxin-induced acute kidney injury by inhibiting NF-κB activities. Sci.

Rep. 2015, 5, 11822. [CrossRef] [PubMed]

Guan, Y.; Wu, X.X.; Duan, J.L.; Yin, Y.; Guo, C.; Wei, G.; Wang, Y.H.; Zhu, Y.R.; Weng, Y.; Xi, M.M.; et al. Effects and Mechanism

of Combination of Rhein and Danshensu in the Treatment of Chronic Kidney Disease. Am. J. Chin. Med. 2015, 43, 1381–1400.

[CrossRef] [PubMed]

Chen, W.; Chang, B.; Zhang, Y.; Yang, P.; Liu, L. Rhein promotes the expression of SIRT1 in kidney tissues of type 2 diabetic rat.

Chin. J. Cell. Mol. Immunol. 2015, 31, 615–619.

Meng, Z.; Yan, Y.; Tang, Z.; Guo, C.; Li, N.; Huang, W.; Ding, G.; Wang, Z.; Xiao, W.; Yang, Z. Anti-hyperuricemic and

nephroprotective effects of rhein in hyperuricemic mice. Planta Med. 2015, 81, 279–285. [CrossRef]

Duan, S.; Wu, Y.; Zhao, C.; Chen, M.; Yuan, Y.; Xing, C.; Zhang, B. The wnt/β-catenin signaling pathway participates in rhein

ameliorating kidney injury in DN mice. Mol. Cell. Biochem. 2016, 411, 73–82. [CrossRef]

Qin, T.; Du, R.; Huang, F.; Yin, S.; Yang, J.; Qin, S.; Cao, W. Sinomenine activation of Nrf2 signaling prevents hyperactive

inflflammation and kidney injury in a mouse model of obstructive nephropathy. Free Radic. Biol. Med. 2016, 92, 90–99. [CrossRef]

Zhang, Q.; Yin, S.; Liu, L.; Liu, Z.; Cao, W. Rhein reversal of DNA hypermethylation-associated Klotho suppression ameliorates

renal fifibrosis in mice. Sci. Rep. 2016, 6, 34597. [CrossRef]

Zhang, Q.; Liu, L.; Lin, W.; Yin, S.; Duan, A.; Liu, Z.; Cao, W. Rhein reverses Klotho repression via promoter demethylation and

protects against kidney and bone injuries in mice with chronic kidney disease. Kidney Int. 2017, 91, 144–156. [CrossRef]

Refaie, M.M.; Amin, E.F.; El-Tahawy, N.F.; Abdelrahman, A.M. Possible Protective Effect of Diacerein on Doxorubicin-Induced

Nephrotoxicity in Rats. J. Toxicol. 2016, 2016, 9507563. [CrossRef]

Tu, Y.; Gu, L.; Chen, D.; Wu, W.; Liu, H.; Hu, H.; Wan, Y.; Sun, W. Rhein Inhibits Autophagy in Rat Renal Tubular Cells by

Regulation of AMPK/mTOR Signaling. Sci. Rep. 2017, 7, 43790. [CrossRef]

Lin, Y.J.; Zhen, Y.Z.; Wei, J.B.; Wei, J.; Dai, J.; Gao, J.L.; Li, K.J.; Hu, G. Rhein lysinate protects renal function in diabetic nephropathy

of KK/HlJ mice. Exp. Ther. Med. 2017, 14, 5801–5808. [CrossRef]

Cao, W.; Bao, C.; Padalko, E.; Lowenstein, C.J. Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like

receptor signaling. J. Exp. Med. 2008, 205, 1491–1503. [CrossRef]

Bi, F.; Chen, F.; Li, Y.; Wei, A.; Cao, W. Klotho preservation by Rhein promotes toll-like receptor 4 proteolysis and attenuates

lipopolysaccharide-induced acute kidney injury. J. Mol. Med. 2018, 96, 915–927. [CrossRef]

Hu, J.; Wu, H.; Wang, D.; Yang, Z.; Zhuang, L.; Yang, N.; Dong, J. Weicao capsule ameliorates renal injury through increasing

autophagy and NLRP3 degradation in UAN rats. Int. J. Biochem. Cell Biol. 2018, 96, 1–8. [CrossRef]Molecules 2022, 27, 6572

18 of 20

Abd-Ellatif, R.N.; Hegab, I.I.; Atef, M.M.; Sadek, M.T.; Hafez, Y.M. Diacerein protects against glycerol-induced acute kidney

injury: Modulating oxidative stress, inflflammation, apoptosis and necroptosis. Chem.-Biol. Int. 2019, 306, 47–53. [CrossRef]

Zeng, X.; Cai, G.; Liang, T.; Li, Q.; Yang, Y.; Zhong, X.; Zou, X.; Qin, M.; Mi, Z. Rhubarb and Astragalus Capsule Attenuates

Renal Interstitial Fibrosis in Rats with Unilateral Ureteral Obstruction by Alleviating Apoptosis through Regulating Transforming

Growth Factor beta1 (TGF-β1)/p38 Mitogen-Activated Protein Kinases (p38 MAPK) Pathway. Med. Sci. Monit. 2020, 26, e920720.

[CrossRef]

Wu, X.; Liu, M.; Wei, G.; Guan, Y.; Duan, J.; Xi, M.; Wang, J. Renal protection of rhein against 5/6 nephrectomied-induced chronic

kidney disease: Role of SIRT3-FOXO3α signalling pathway. J. Pharm. Pharmacol. 2020, 72, 699–708. [CrossRef]

Hu, J.; Yang, Z.; Wu, H.; Wang, D. Rhein attenuates renal inflflammatory injury of uric acid nephropathy via lincRNA-Cox2/miR-

150-5p/STAT1 axis. Int. Immunopharmacol. 2020, 85, 106620. [CrossRef] [PubMed]

Liu, M.; Wang, L.; Wu, X.; Gao, K.; Wang, F.; Cui, J.; Zhao, J.; Peng, L.; Wang, J.; Jia, Y.; et al. Rhein protects 5/6 nephrectomized rat

against renal injury by reducing inflflammation via NF-κB signaling. Int. Urol. Nephrol. 2021, 53, 1473–1482. [CrossRef] [PubMed]

Wang, Y.N.; Wu, X.Q.; Zhang, D.D.; Hu, H.H.; Liu, J.L.; Vaziri, N.D.; Guo, Y.; Zhao, Y.Y.; Miao, H. Polyporus Umbellatus Protects

Against Renal Fibrosis by Regulating Intrarenal Fatty Acyl Metabolites. Front. Pharmacol. 2021, 12, 633566. [CrossRef]

Luo, L.P.; Suo, P.; Ren, L.L.; Liu, H.J.; Zhang, Y.; Zhao, Y.Y. Shenkang Injection and Its Three Anthraquinones Ameliorates

Renal Fibrosis by Simultaneous Targeting IÎB/NF-ÎB and Keap1/Nrf2 Signaling Pathways. Front. Pharmacol. 2021, 12, 800522.

[CrossRef] [PubMed]

Chen, Q.; Guo, H.; Hu, J.; Zhao, X. Rhein Inhibits NF-κB Signaling Pathway to Alleviate Inflflammatory Response and Oxidative

Stress of Rats with Chronic Glomerulonephritis. Appl. Bionics Biomech. 2022, 2022, 9671759. [CrossRef] [PubMed]

Xiao, Q.; Yu, X.; Yu, X.; Liu, S.; Jiang, J.; Cheng, Y.; Lin, H.; Wang, Y.; Zhang, X.; Ye, X.; et al. An integrated network pharmacology

and cell metabolomics approach to reveal the role of rhein, a novel PPARα agonist, against renal fifibrosis by activating the

PPARα-CPT1A axis. Phytomedicine 2022, 102, 154147. [CrossRef]

Kiritoshi, S.; Nishikawa, T.; Sonoda, K.; Kukidome, D.; Senokuchi, T.; Matsuo, T.; Matsumura, T.; Tokunaga, H.; Brownlee,

M.; Araki, E. Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells:

Potential role in diabetic nephropathy. Diabetes 2003, 52, 2570–2577. [CrossRef]

Dai, C.S.L.Z.; Chen, H.P. Effects of rhein on inhibiting the progression of diabetic nephropathy in STZ-induced diabetic rats. J.

Nephrol. Dial. Transpl. 1998, 8, 413–505.

Masson, E.; Lagarde, M.; Wiernsperger, N.; El Bawab, S. Hyperglycemia and glucosamine-induced mesangial cell cycle arrest and

hypertrophy: Common or independent mechanisms? IUBMB Life 2006, 58, 381–388. [CrossRef]

Inoki, K.; Haneda, M.; Maeda, S.; Koya, D.; Kikkawa, R. TGF-beta 1 stimulates glucose uptake by enhancing GLUT1 expression in

mesangial cells. Kidney Int. 1999, 55, 1704–1712. [CrossRef]

Chen, H.C.; Guh, J.Y.; Chang, J.M.; Hsieh, M.C.; Shin, S.J.; Lai, Y.H. Role of lipid control in diabetic nephropathy. Kidney Int. 2005,

67, S60–S62. [CrossRef]

Usui, H.; Shikata, K.; Matsuda, M.; Okada, S.; Ogawa, D.; Yamashita, T.; Hida, K.; Satoh, M.; Wada, J.; Makino, H. HMG-CoA

reductase inhibitor ameliorates diabetic nephropathy by its pleiotropic effects in rats. Nephrol. Dial. Transplant. 2003, 18, 265–272.

[CrossRef]

Wang, W.; Sun, W.; Cheng, Y.; Xu, Z.; Cai, L. Role of sirtuin-1 in diabetic nephropathy. J. Mol. Med. 2019, 97, 291–309. [CrossRef]

Okada, T.; Nakao, T.; Matsumoto, H.; Shino, T.; Nagaoka, Y.; Tomaru, R.; Wada, T. Association between markers of glycemic

control, cardiovascular complications and survival in type 2 diabetic patients with end-stage renal disease. Int. Med. 2007,

46, 807–814. [CrossRef]

Li, J.; Wang, J.J.; Yu, Q.; Wang, M.; Zhang, S.X. Endoplasmic reticulum stress is implicated in retinal inflflammation and diabetic

retinopathy. FEBS Lett. 2009, 583, 1521–1527. [CrossRef]

Hotamisligil, G.S. Endoplasmic reticulum stress and the inflflammatory basis of metabolic disease. Cell 2010, 140, 900–917.

[CrossRef]

Martinon, F.; Pétrilli, V.; Mayor, A.; Tardivel, A.; Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflflammasome.

Nature 2006, 440, 237–241. [CrossRef]

Schlesinger, N. Management of acute and chronic gouty arthritis: Present state-of-the-art. Drugs 2004, 64, 2399–2416. [CrossRef]

Chen, I.H.; Kuo, M.C.; Hwang, S.J.; Chang, J.M.; Chen, H.C. Allopurinol-induced severe hypersensitivity with acute renal failure.

Kaohsiung J. Med. Sci. 2005, 21, 228–232. [CrossRef]

Huang, M.D.; Chen, W.M.; Qi, F.Z.; Xia, R.; Sun, M.; Xu, T.P.; Yin, L.; Zhang, E.B.; De, W.; Shu, Y.Q. Long non-coding RNA ANRIL

is upregulated in hepatocellular carcinoma and regulates cell proliferation by epigenetic silencing of KLF2. J. Hematol. Oncol.

2015, 8, 57. [CrossRef] [PubMed]

Pasmant, E.; Sabbagh, A.; Vidaud, M.; Bièche, I. ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS.

FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2011, 25, 444–448. [CrossRef] [PubMed]

Rapicavoli, N.A.; Qu, K.; Zhang, J.; Mikhail, M.; Laberge, R.M.; Chang, H.Y. A mammalian pseudogene lncRNA at the interface

of inflflammation and anti-inflflammatory therapeutics. eLife 2013, 2, e00762. [CrossRef] [PubMed]

Hu, G.; Gong, A.Y.; Wang, Y.; Ma, S.; Chen, X.; Chen, J.; Su, C.J.; Shibata, A.; Strauss-Soukup, J.K.; Drescher, K.M.; et al.

LincRNA-Cox2 Promotes Late Inflflammatory Gene Transcription in Macrophages through Modulating SWI/SNF-Mediated

Chromatin Remodeling. J. Immunol. 2016, 196, 2799–2808. [CrossRef] [PubMed]Molecules 2022, 27, 6572

19 of 20

Hoste, E.A.; Lameire, N.H.; Vanholder, R.C.; Benoit, D.D.; Decruyenaere, J.M.; Colardyn, F.A. Acute renal failure in patients with

sepsis in a surgical ICU: Predictive factors, incidence, comorbidity, and outcome. J. Am. Soc. Nephrol. JASN 2003, 14, 1022–1030.

[CrossRef] [PubMed]

Lafrance, J.P.; Miller, D.R. Acute kidney injury associates with increased long-term mortality. J. Am. Soc. Nephrol. JASN 2010,

21, 345–352. [CrossRef]

Wald, R.; Shariff, S.Z.; Adhikari, N.K.; Bagshaw, S.M.; Burns, K.E.; Friedrich, J.O.; Garg, A.X.; Harel, Z.; Kitchlu, A.; Ray, J.G. The

association between renal replacement therapy modality and long-term outcomes among critically ill adults with acute kidney

injury: A retrospective cohort study. Crit. Care Med. 2014, 42, 868–877. [CrossRef]

Kinsey, G.R.; Li, L.; Okusa, M.D. Inflflammation in acute kidney injury. Nephron. Exp. Nephrol. 2008, 109, e102–e107. [CrossRef]

van Es, L.A.; van den Wall Bake, A.W.; Valentijn, R.M.; Daha, M.R. Composition of IgA-containing circulating immune complexes

in IgA nephropathy. Am. J. Kidney Dis. 1988, 12, 397–401. [CrossRef]

Baldree, L.A.; Wyatt, R.J.; Julian, B.A.; Falk, R.J.; Jennette, J.C. Immunoglobulin A-fifibronectin aggregate levels in children and

adults with immunoglobulin A nephropathy. Am. J. Kidney Dis. 1993, 22, 1–4. [CrossRef]

Floege, J.; Amann, K. Primary glomerulonephritides. Lancet 2016, 387, 2036–2048. [CrossRef]
Zou, J.J.; Zhou, X.T.; Chen, Y.K.; Liu, J.L.; Wang, C.; Ma, Y.R.; Wang, L. A review on the effificacy and mechanism of action of

Shenkang injection against chronic kidney disease. Biomed. Pharmacother. 2020, 132, 110833. [CrossRef]

Briganti, E.M.; Dowling, J.; Finlay, M.; Hill, P.A.; Jones, C.L.; Kincaid-Smith, P.S.; Sinclair, R.; McNeil, J.J.; Atkins, R.C. The

incidence of biopsy-proven glomerulonephritis in Australia. Nephrol. Dial. Transplant. 2001, 16, 1364–1367. [CrossRef]

Sato, D.; Suzuki, Y.; Kano, T.; Suzuki, H.; Matsuoka, J.; Yokoi, H.; Horikoshi, S.; Ikeda, K.; Tomino, Y. Tonsillar TLR9 expression and

effificacy of tonsillectomy with steroid pulse therapy in IgA nephropathy patients. Nephrol. Dial. Transplant. 2012, 27, 1090–1097.

[CrossRef]

Zhao, Y.; Banerjee, S.; Dey, N.; LeJeune, W.S.; Sarkar, P.S.; Brobey, R.; Rosenblatt, K.P.; Tilton, R.G.; Choudhary, S. Klotho depletion

contributes to increased inflflammation in kidney of the db/db mouse model of diabetes via RelA (serine)536 phosphorylation.

Diabetes 2011, 60, 1907–1916. [CrossRef]

Buendía, P.; Carracedo, J.; Soriano, S.; Madueño, J.A.; Ortiz, A.; Martín-Malo, A.; Aljama, P.; Ramírez, R. Klotho Prevents NFκB

Translocation and Protects Endothelial Cell From Senescence Induced by Uremia. J. Gerontol. 2015, 70, 1198–1209. [CrossRef]

Esposito, C.; Dal Canton, A. Functional changes in the aging kidney. J. Nephrol. 2010, 23 (Suppl. 15), S41–S45.
Takeda, T.; Hosokawa, M.; Higuchi, K. Senescence-accelerated mouse (SAM): A novel murine model of senescence. Exp. Gerontol.

1997, 32, 105–109. [CrossRef]

Mazer, M.; Perrone, J. Acetaminophen-induced nephrotoxicity: Pathophysiology, clinical manifestations, and management. J.

Med. Toxicol. 2008, 4, 2–6. [CrossRef]

Somani, S.M.; Husain, K.; Whitworth, C.; Trammell, G.L.; Malafa, M.; Rybak, L.P. Dose-dependent protection by lipoic acid

against cisplatin-induced nephrotoxicity in rats: Antioxidant defense system. Pharmacol. Toxicol. 2000, 86, 234–241. [CrossRef]

Hensley, K.; Robinson, K.A.; Gabbita, S.P.; Salsman, S.; Floyd, R.A. Reactive oxygen species, cell signaling, and cell injury. Free

Radic. Biol. Med. 2000, 28, 1456–1462. [CrossRef]

Koyama, T.; Kume, S.; Koya, D.; Araki, S.; Isshiki, K.; Chin-Kanasaki, M.; Sugimoto, T.; Haneda, M.; Sugaya, T.; Kashiwagi,

A.; et al. SIRT3 attenuates palmitate-induced ROS production and inflflammation in proximal tubular cells. Free Radic. Biol. Med.

2011, 51, 1258–1267. [CrossRef] [PubMed]

Fattah, H.; Vallon, V. Tubular Recovery after Acute Kidney Injury. Nephron 2018, 140, 140–143. [CrossRef] [PubMed]
Falke, L.L.; Gholizadeh, S.; Goldschmeding, R.; Kok, R.J.; Nguyen, T.Q. Diverse origins of the myofifibroblast—implications for

kidney fifibrosis. Nat. Rev. Nephrol. 2015, 11, 233–244. [CrossRef]

Tzavlaki, K.; Moustakas, A. TGF-β Signaling. Biomolecules 2020, 10, 487. [CrossRef]
Frangogiannis, N. Transforming growth factor-β in tissue fifibrosis. J. Exp. Med. 2020, 217, e20190103. [CrossRef]
Edeling, M.; Ragi, G.; Huang, S.; Pavenstädt, H.; Susztak, K. Developmental signalling pathways in renal fifibrosis: The roles of

Notch, Wnt and Hedgehog. Nat. Rev. Nephrol. 2016, 12, 426–439. [CrossRef]

Meng, X.M.; Chung, A.C.; Lan, H.Y. Role of the TGF-β/BMP-7/Smad pathways in renal diseases. Clin. Sci. 2013, 124, 243–254.

[CrossRef]

Kim, S.I.; Kwak, J.H.; Zachariah, M.; He, Y.; Wang, L.; Choi, M.E. TGF-beta-activated kinase 1 and TAK1-binding protein 1

cooperate to mediate TGF-beta1-induced MKK3-p38 MAPK activation and stimulation of type I collagen. Am. J. Physiol. Ren.

Physiol. 2007, 292, F1471–F1478. [CrossRef]

Alcorn, J.F.; van der Velden, J.; Brown, A.L.; McElhinney, B.; Irvin, C.G.; Janssen-Heininger, Y.M. c-Jun N-terminal kinase 1 is

required for the development of pulmonary fifibrosis. Am. J. Respir. Cell Mol. Biol. 2009, 40, 422–432. [CrossRef]

Lin, Y.L.; Wu, C.F.; Huang, Y.T. Effects of rhubarb on migration of rat hepatic stellate cells. J. Gastroenterol. Hepatol. 2009,

24, 453–461. [CrossRef]

Li, H.; Xu, Y.; Zhang, Q.; Xu, H.; Xu, Y.; Ling, K. Microvesicles containing miR-34a induce apoptosis of proximal tubular epithelial

cells and participate in renal interstitial fifibrosis. Exp. Ther. Med. 2019, 17, 2310–2316. [CrossRef]

Boulter, E.; Van Obberghen-Schilling, E. Integrin-linked kinase and its partners: A modular platform regulating cell-matrix

adhesion dynamics and cytoskeletal organization. Eur. J. Cell Biol. 2006, 85, 255–263. [CrossRef]Molecules 2022, 27, 6572

20 of 20

Bai, Y.; Wang, L.; Li, Y.; Liu, S.; Li, J.; Wang, H.; Huang, H. High ambient glucose levels modulates the production of MMP-9 and

alpha5(IV) collagen by cultured podocytes. Cell. Physiol. Biochem. 2006, 17, 57–68. [CrossRef]

Wang, X.Y.; Wang, Y.; Liu, H.C. Tamoxifen lowers the MMP-9/TIMP-1 ratio and inhibits the invasion capacity of ER-positive

non-small cell lung cancer cells. Biomed. Pharmacother. 2011, 65, 525–528. [CrossRef]

Troussard, A.A.; Costello, P.; Yoganathan, T.N.; Kumagai, S.; Roskelley, C.D.; Dedhar, S. The integrin linked kinase (ILK) induces

an invasive phenotype via AP-1 transcription factor-dependent upregulation of matrix metalloproteinase 9 (MMP-9). Oncogene

2000, 19, 5444–5452. [CrossRef]

Guan, Y. Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome.
Am. Soc. Nephrol. JASN 2004, 15, 2801–2815. [CrossRef]
Kuro-o, M.; Matsumura, Y.; Aizawa, H.; Kawaguchi, H.; Suga, T.; Utsugi, T.; Ohyama, Y.; Kurabayashi, M.; Kaname, T.; Kume,

E.; et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997, 390, 45–51. [CrossRef]

Kuro, O.M. The FGF23 and Klotho system beyond mineral metabolism. Clin. Exp. Nephrol. 2017, 21, 64–69. [CrossRef]
Liu, M.; Liu, T.; Shang, P.; Zhang, Y.; Liu, L.; Liu, T.; Sun, S. Acetyl-11-keto-β-boswellic acid ameliorates renal interstitial fifibrosis

via Klotho/TGF-β/Smad signalling pathway. J. Cell. Mol. Med. 2018, 22, 4997–5007. [CrossRef]

Cho, N.J.; Han, D.J.; Lee, J.H.; Jang, S.H.; Kang, J.S.; Gil, H.W.; Park, S.; Lee, E.Y. Soluble klotho as a marker of renal fifibrosis and

podocyte injuries in human kidneys. PLoS ONE 2018, 13, e0194617. [CrossRef] [PubMed]

Tampe, B.; Zeisberg, M. Contribution of genetics and epigenetics to progression of kidney fifibrosis. Nephrol. Dial. Transplant. 2014,

29 (Suppl. 4), iv72–iv79. [CrossRef] [PubMed]

Liu, T.; Meng, Q.; Wang, C.; Liu, Q.; Guo, X.; Sun, H.; Peng, J.; Ma, X.; Kaku, T.; Liu, K. Changes in expression of renal Oat1, Oat3

and Mrp2 in cisplatin-induced acute renal failure after treatment of JBP485 in rats. Toxicol. Appl. Pharmacol. 2012, 264, 423–430.

[CrossRef] [PubMed]

Feng, S.X.; Li, J.S.; Qu, L.B.; Shi, Y.M.; Zhao, D. Comparative pharmacokinetics of fifive rhubarb anthraquinones in normal and

thrombotic focal cerebral ischemia-induced rats. Phytother. Res. PTR 2013, 27, 1489–1494. [CrossRef]

Da, H.Y.; Jiang, Z.Z.; Wang, C.F.; Zhang, L.Y.; Liu, G.Q. The toxic effects of rhein and emodin on human renal tubular epithelial

cells in vitro. Chin. Tradit. Herb. Drug 2009, 40, 102–105.

Yang, J.P.; Sun, H.; Wang, D.D.; Mao, Y.Y.F. MAPK Signal Transduction Pathway involves in Rhein-induced Apoptosis in HK-2

Cells. Chi. J. Exp. Tradit. Med. Formulae 2015, 21, 147–151.

Sun, H.; Yang, J.P.; Mao, Y.; Wang, D.D.; Yu, F. Involvement of Fas-dependent pathway in rhein-induced apoptosis of HK- 2 cells.
China Pharm. Univ. 2015, 46, 469–475.
Mao, Y.; Zhang, M.; Yang, J.; Sun, H.; Wang, D.; Zhang, X.; Yu, F.; Li, J. The UCP2-related mitochondrial pathway participates in

rhein-induced apoptosis in HK-2 cells. Toxicol. Res. 2017, 6, 297–304. [CrossRef]

Hu, Y.F.; Huang, W.Y.; Li, Y.Q.; Luo, Y.; Jiang, Q.; Liang, Y.S.; Zhu, Z.W.; Wang, P.; Meng, X.L. Mechanism of Rhein on Renal

Toxicity of Mice. Chin. J. Exp. Tradit. Med. Formulae 2019, 25, 54–59.

Faitova, J.; Krekac, D.; Hrstka, R.; Vojtesek, B. Endoplasmic reticulum stress and apoptosis. Cell. Mol. Biol. Lett. 2006, 11, 488–505.

[CrossRef]

Lai, Y. Effects of Compatibility of Rhubarb and Huangqi on the Toxicity and Oxidative Stress of Rhubarb On HK-2 Cells. Ph.D.

Thesis, Guangzhou University of Chinese Medicine, Guangzhou, China, May 2018.