Natural Product Therapies in Chronic Kidney Diseases

Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com

Yue Qiu ^a, Yang Qiu ^a, Guang-Min Yao^b, Changqing Luo ^a, **, Chun Zhang ^a,* et al

Abstract:

Chronic kidney disease is one of the major worldwide public health problems. Traditional Chinese medications have been widely used for chronic kidney disease treatment. With the development of modern phytochemistry technology, natural products have been isolated from traditional Chinese medications, which provide a more precise method for the investigation of traditional Chinese medications. In this article, we selected eight natural products from traditional Chinese medications for chronic kidney disease therapy to summarize the recent advances in the development of new medications.

Keywords: Chronic kidney disease natural products traditional Chinese medications

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1. Introduction

Chronic kidney disease (CKD) is a global public health problem with poor prognosis and limited intervention. 10% of the population worldwide is affected by CKD with high mortality [1]. In 2012, 1.5% of deaths worldwide were attributed to CKD [2]. The main medications for CKD are renin-angiotensin system (RAS) blockers, steroids, and immune suppressants. However, the positive effects of RAS blockers are limited [3]. Meanwhile, the side effects of steroids and immune suppressants are, including infection and cancer [4]. Therefore, effective medications for CKD with fewer side effects are urgently needed.

Traditional Chinese medications (TCMs) have been used to treat a variety of diseases for more than 2,000 years. In China and other Asian countries, TCMs have been chosen as alternative therapies for CKD. The fundamental principle of TCMs application is to regulate the Yin and Yang balance in the whole-body system [5]. TCMs are mainly based on recorded empirical experiences and the combined effects of different plant medicines. The introduction of traditional Chinese medicine in France could date back to the 1920s when acupuncture was brought to French doctors [6]. And some botany, which was used in traditional Chinese medicine, was also applied in France for a long history, such as Crataegus pinnatifid [7]. Until 2006, there were more than 18,000 Chinese medicine clinics in Europe, and the therapeutic effects of traditional Chinese medicine have been realized increasingly [8,9].

Modern pharmacology contributes to the advances of TCMs in terms of isolating and screening active compounds. It is reported that TCM-related modern pharmacology successfully helps to isolate the anti-malaria agent artemisinin (qinghaosu) from Artemisia annua, which was thus awarded Nobel Prize in Physiology or Medicine in 2015. Moreover, it has saved millions of lives around the world till 2015 [10]. For another example, triptolide from Tripterygium Hook F was approved to have a podocyte protective effect in animal models of membranous nephropathy [11]. The development of natural products gives rise to a more precise manner for TCMs.

This review illustrates the six most frequently used herbal medications for kidney disease therapy in China, the efficiencies and mechanisms of eight major ingredients isolated from them, as well as the most recent advances in CKD therapy (Table 1).

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2. Compounds and their corresponding medications

2.1. Triptolide and celastrol

Tripterygium Hook F (TwHF), known as Lei Gong Teng (Thunder God Vine), has been used for rheumatoid arthritis and CKD treatment since the 1970s in China [12,13]. Most publications on the clinical effects of TwHF in kidney disease therapy were in regional journals. Bin et al. made a meta-analysis of the clinical trials reported in Chinese on the application of Tripterygium preparations (Tripterygium glycoside tablets, Tripterygium Hutch tablets, and Tripterygium granules or extracts) for CKD therapy [14]. There were also published clinical trials in English. Yongchun et al. reported that TwHF extract could reduce proteinuria in diabetic nephropathy patients in a prospective randomized clinical trial [15].

TwHF contains a variety of natural products, the major and effective ingredients including triptolide and celastrol (CLT) with potent anti-inflammatory and immunosuppressive functions [16]

2.1.1. Triptolide

Triptolide is a diterpenoid epoxide, with a potent anti-inflammatory function. In vitro study showed that triptolide significantly inhibits three key pro-inflammatory genes induced by lipopolysaccharide (LPS) in mouse RAW 264.7 macrophages: cyclooxygenase-2 (COX-2) (IC50 = 0.03 mM), inducible nitric oxide synthase (iNOS) (IC50 = 0.04 mM), and interleukin-1b (IL-1b) (IC50 = 0.01 mM) [17]. However, the molecular mechanisms underlying the effects of triptolide on pro-inflammatory genes are not fully understood. XPB/ERCC3, a subunit of the transcription factor TFIIH, is identified as the target gene of COX-2. Triptolide hinders RNA Polymerase II-mediated transcription and nucleotide excision repair by targeting XPB/ERCC3, thus showing anti-proliferative and anti-inflammation activities [18]. Moreover, triptolide promotes pancreatic cancer cell apoptosis via inhibition of heat shock protein 70 (HSP 70) [19]. Moreover, chronic triptolide (0.2 mg/kg/d for 60 days) administration in mice was reported to inhibit pancreatic cancer growth and metastasis [19].

To the renal resident cells, triptolide protects podocytes from puromycin aminonucleoside (PAN) [20] and C5b-9 [21] induced injury by inactivating reactive oxygen species (ROS) mediated p38 mitogen-activated protein kinase (MAPK) pathway. Inactivated human proximal tubular epithelial cells, triptolide suppresses C3, CD40, and B7h expressions via anti-inflammation and immune modulation. Triptolide is more effective than cyclosporine A and tacrolimus in the inhibition of C3 expression [22].

Triptolide is effective in several proteinuria models, such as PAN-induced focal segmental glomerular sclerosis [20], passive Heymann nephritis [21], and diabetic nephropathy [23]. In autosomal dominant polycystic kidney disease (ADPKD), triptolide effectively reduces cystogenesis and protects renal function [24].

Recent advances: In mice renal allograft transplantation, triptolide inhibits donor-specific antibody production and immune cell infiltration, attenuating antibody-mediated renal injury by both innate and adaptive immune responses [25].

2.1.2. Celastrol

CLT, a triterpene, was first identified as a heat shock protein 90 (HSP 90) inhibitor in prostate cancer cells, by inducing the degradation of HSP 90 [26]. CLT also promotes the dephosphorylation and degradation of HSP90/CDC37 client protein kinases, which suppresses cellular proliferation but advances cellular apoptosis [27].

CLT is effective in ischemia-reperfusion-induced acute kidney injury (AKI) rats by inhibition of nuclear translation of nuclear factor-kappaB (NF-kB) p65 [28]. CLT is also known as a potent anti-fibrotic ingredient. It alleviates renal fibrosis in unilateral ureteral obstruction (UUO) mice model by upregulating cannabinoid receptor 2 expression, which is a specific metabotropic receptor of the endocannabinoid system playing an important role in inflammation and fibrosis processes [29].

CLT is highly effective in CKD treatment, but its toxicity, which originates from TwHF cannot be ignored. Recently, CLT-loaded albumin nanoparticles were found to effectively reduce the toxicity of CLT in the Thy1.1 mesangial proliferative glomerulonephritis mice model by targeting mesangial cells [30].

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2.2. Astragaloside IV

Astragalus, also called Huangqi, is derived from the root of the Leguminosae plant Astragalus membrane or Astragalus mongo. In recent years, Astragalus is reported to be involved in anti-inflammatory, immunostimulant, antioxidative, anticancer, and antiviral effects [31]. It has also been used for renal diseases treatment for over 2,000 years, which was recorded in Shen Nong’s Materia Medica [31].

Astragaloside IV (AS-IV) is one of the most abundant and active compounds isolated from Astragalus, with potent immune regulatory effects [32]. Briefly, it inactivates glycation end product-stimulated macrophages via phosphate-p38 MAPK and NF-kB pathways [33]. AS-IV could also increase T, B lymphocyte proliferation in vitro [34]. AS-IV alleviates T regulatory cells suppression by proinflammatory cytokine high mobility group box 1 protein in vitro [35].

For renal parenchyma cells, AS-IV attenuates glycated albumin-induced epithelial-mesenchymal transition (EMT) in the NRK-52E cell line via balancing redox [34]. AS-IV could inhibit high glucose (HG) induced cell apoptosis by suppressing the p38 MAPK pathway in human tubular epithelial cells [36]. AS-IV improves HG-induced podocyte dysfunction via a3b integrin upregulation and integrin-linked kinase inhibition [37].

For animal models, AS-IV prevents AKI in ischemia-reperfusion and contrast-induced AKI rat and cisplatin (CP)-mediated AKI mice by inhibiting oxidative stress and apoptosis [38,39]. AS-IV also ameliorates renal injury in streptozotocin-induced diabetic rats via inhibition of inflammation induced by the NF-kB pathway [40].

Recent advances: AS-IV is found to inhibit miR-21-induced podocyte dedifferentiation and mesangial cell activation, thus improving renal function and attenuating fibrosis in diabetic mice [41].

2.3. Emodin and Rhein

Rheum Officinale (Da Huang), an herbal plant, has been widely used in China for its strong cathartic effect. Recently, it has been used to slow down CKD progression. The mechanisms involved in CKD therapy include squalene epoxidase inhibition [42] and anti-fibrotic effect [43]. Emodin and Rhein are two of the most important components isolated from Rheum Officinale [44].

2.3.1. Emodin

Emodin presents various pharmacological properties, such as anti-apoptosis, anti-oxidant, anti-EMT, anti-fibrosis, and anti-inflammation activities. In detail, emodin ameliorates CP-induced apoptosis of rat renal tubular cells in vitro by modulating the AMPK/mTOR signaling pathway [45]. Moreover, it protects against oxidative stress and hypoxia/reoxygenation-induced apoptosis of HK-2 cells [46]. Emodin ameliorates HG-induced podocyte EMT [47]. Emodin attenuates HG-induced transforming growth factor-beta 1 (TGF-b1) and fibronectin expression in mesangial cells through the inhibition of the NF-kB pathway [48]. Emodin suppresses HG-induced proliferation and fibronectin expression in rat mesangial cells via the p38 MAPK pathway [49].

Emodin is effective in LPS induced AKI via the inhibition of inflammation and the Toll-like receptor 2 pathway [50]. It protects against diabetic nephropathy in rat models mediated by PI3K/Akt/ GSK-3b and Bax/caspase-3 signaling pathways [51]. Moreover, it is effective in CP-induced nephrotoxicity in rats [52].

2.3.2. Rhein

Rhein exhibits various renal protective functions; however, the underlying mechanisms are not fully determined. In vitro, it inhibits autophagy in rat renal tubular cells by regulating the AMPK/ mTOR signaling pathway [53]. Rhein promotes toll-like receptor 4 proteolysis and attenuates lipopolysaccharide-induced AKI via the preservation of Klotho [54]. Rhein restores Klotho abundance in adenine-induced CKD mice, which is mainly mediated by demethylation promoters [55]. Rhein reverses Klotho suppression, which is associated with DNA hypermethylation, thus ameliorating renal fibrosis in mice [56]. Preventive effects of rhein are demonstrated on UUO nephropathy mice [57].

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2.4. H1-A

Cordyceps Sinensis (CS), also known as Chinese caterpillar fungus, is effective in modulating immune responses [58]. CS has been widely used as a formulated capsule for CKD patients.

H1-A, one of the major secondary metabolites from CS [58], plays an important role in the inhibition of human mesangial cell proliferation. It promotes cellular apoptosis by suppressing the tyrosine phosphorylation of Bcl-2 and Bcl-XL [59,60]. H1-A can also be used for IgA nephropathy with clinical and histologic improvement [60].

2.5. Saikosaponin d

Radix bupleuri (Chai hu) is the dry roots of Bupleurum chinense DC. and Bupleurum scorzonerifolium Willd [61]. Triterpenoid saponins are the major bioactive components extracted from Radix bleu [62], among which Daikin d (SSD) is one of the most important Saiko saponins, with anti-inflammatory, antitumor, and immunoregulation activities [63].

SSD, known as sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump inhibitor, induces autophagic cell death in apoptosis-defective cells [64]. It inhibits proliferation by up-regulating autophagy via the CaMKKb-AMPK-mTOR pathway in ADPKD cells [65].

SSD reduces CP-induced nephrotoxicity by repressing ROS-mediated activation of MAPK and NF-kB signaling pathways [66]. It also causes mesangial cells proliferation inhibition, but not cell death, which is mediated by the downregulation of CDK4, c-Jun, and c-Fos [67]. SSD is effective in Thy1.1-induced metro literature glomerulonephritis via the reduction of TGF-b1 abundance and inflammatory cells [68].

2.6. Poricoic acid ZA

The dried sclerotia of Poria cocos Wolf (WPC) has been used for treating chronic edema and nephrosis. WPC improves PAN-induced nephrosis by inhibition of water and sodium channels, thus improving edema and nephrosis [69]. WPC inhibits HG-induced proliferation of rat mesangial cells [70]. Portico acid ZA, a novel RAS inhibitor, is extracted from WPC. It attenuates interstitial fibrosis and podocyte injury by inhibiting the TGF-b/Smad signaling pathway [71].

3. Perspective

TCM, on one hand, has therapeutic effects in CKD therapy, on the other hand, the toxicity of herbal medications could not be neglected [5]. The detoxifying measures of herbs in the ancient way, which is called ‘PaoZhi’ in Chinese, could reduce the toxicity of herbs to become prescribed TCMs [72]. Moreover, the traditional compatibility of TCMs is the principle of the Monarch-Minister Assistant-Guide, which is also named ‘Jun-Chen-Zuo-Shi’ in Chinese. The assistants are the herbs, which have an antagonist effect on the toxicity of TCM prescriptions [73].

For the sights of modern pharmacology, the isolation of effective compounds and toxic components could bring qualification to the TCMs. However, some effective compounds, such as triptolide and celastrol, also have toxic side-effect. Further investigation for the dosage and duration needs a clinical trial. And vector, which could reduce the toxic effect of medications, is one of the future research directions [30].

4. Conclusion

TCMs have a long history in the treatment of CKD. AlthoughTCMs are widely applied in a clinic in China, their exact mechanisms of them are not fully understood. Moreover, the application of TCM is mainly based on personal experience, which lacks evaluation standards. Isolation technology provides new insight into the precise application of TCMs. Many highly effective compounds are proved to have anti-inflammatory, anti-oxidative, or immunomodulatory effects. Some of them not only present protective effects on renal parenchymal cells directly but are also effective in animal models. These effective natural products have great translational potential for the precision use of TCMs. Also, large clinical trials are needed for the TCMs and their extractions in CKD therapy.

Disclosure of interest

The authors declare that they have no competing interests.

Acknowledgments

This work was supported by grants from the National NaturalScience Foundation of China (No. 81974096, No. 81961138007, No.81770711), the National Key R&D Program of China(2018YFC1314000), and the Program for HUST Academic FrontierYouth Team (2017QYTD20).

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