Use of fucoidan to treat renal diseases: A review of 15 years of clinic studies

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Use of fucoidan to treat renal diseases: A review of 15 years of clinic studies Jing Wanga,b,c,*, Lihua Genga,b,c, Yang Yuea,b,c, Quanbin Zhanga,b,c,* a

Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China b Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China c Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, China *Corresponding authors: e-mail address: [email protected]; [email protected]

Contents 1. Introduction 2. Preparation and structure of fucoidan 3. Pharmacology and mechanism of fucoidan 3.1 Chronic renal failure (CRF) 3.2 Acute kidney injury (AKI) 3.3 Diabetic nephropathy (DN) 4. Clinical uses and efficacy of fucoidan 5. Future perspectives Acknowledgments References

2 3 5 5 7 8 9 12 12 13

Abstract Fucoidan is a sulfated polysaccharide extracted from brown seaweeds. Studies have shown that fucoidan has curative effects on the chronic renal failure, acute kidney injury, and diabetic nephropathy both in vitro and in vivo. Saccharina japonica is the most economically important brown seaweed cultivated in China and is consumed as a marine vegetable in East Asia. Over the past thousand years, Chinese people have traditionally used this plant to cure edema, a symptom of kidney diseases. The fucoidan extracted from Saccharina japonica is composed primarily of fucose and galactose with smaller amounts of other monosaccharides. Structure–activity relationship studies reveal that the molecular weight, monosaccharide compositions, the sulfation degree and the positions of sulfates influences the renoprotective activity. Low molecular weight fucoidan exhibits better activity than fucoidan. Pharmacological studies indicate that fucoidan inhibits renal fibrosis and glomerular sclerosis by reducing the accumulation of extracellular matrix. In addition, fucoidan reduces the inflammatory response and P-selectin expression, maintains the glomerular basement membrane

Progress in Molecular Biology and Translational Science ISSN 1877-1173 https://doi.org/10.1016/bs.pmbts.2019.03.011

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2019 Elsevier Inc. All rights reserved.

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and glomerular structural integrity, improves glomerular filtration function, and protects renal glycosaminoglycans from abnormal degradation. The effective constituent of Haikun Shenxi capsule (HSC) is the fucoidan extracted from Saccharina japonica. HSC was approved for treating renal diseases by the Chinese Food and Drug Administration in 2003. Based on the results of peer-reviewed publications, we will recapitulate the structure, pharmacology, reported clinical cases, clinical efficacy, and future perspectives of HSC. This review will summarize the knowledge of HSC gained in China to stimulate in-depth academic and clinical studies of HSC world widely.

1. Introduction As a result of the unique nature of their living environment, marine organisms have produced and accumulated a large number of substances with special chemical structures, physiological activities, and functions during their growth and metabolism.1,2 Fucoidan, extracted from brown seaweeds, such as Saccharina japonica, Sargassum thunbergii, Fucus vesiculosus, and Ascopbyllum nodosum, is a sulfated polysaccharide that is composed primarily of fucose, galactose and sulfate, with smaller amounts of mannoses, uronic acid, glucose, rhamnose, arabinose, and xylose. Fucoidans are reported to possess potentially diverse medicinal values, such as antioxidant, anti-inflammatory, reno-protective, antitumor, antiobesity, anticoagulant, antiviral, antihepatopathy, antiuropathy, and antirenopathy activities.1 Saccharina japonica is a popular seafood in China and in many other countries. During the past thousands of years, Chinese people have used this seaweed as a traditional medicine for curing edema, a symptom of kidney diseases.3 Our previous study found the fucoidan extracted from Saccharina japonica exhibits reno-protective activity both in vitro and in vivo. The main effect of fucoidan is to increase renal blood flow and diuresis and reduce blood creatinine, urea nitrogen, and proteinuria.4 Fucoidan reduces the accumulation of the extracellular matrix and inhibits renal fibrosis and glomerular sclerosis. Chronic renal failure (CRF), acute kidney injury (AKI) and diabetic nephropathy (DN) are three common types of renal diseases. Chronic renal failure (CRF) is associated with the progressive renal damage caused by various primary or secondary chronic kidney diseases (CKDs), and exhibits a clinical syndrome with a series of symptoms or metabolic disorders.5 CRF is a global public health problem and is prevalent in many countries. It is estimated that over $1 trillion is spent globally on end-stage renal disease (ESRD).6

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Acute Kidney Injury (AKI) is a clinical syndrome characterized by the rapid decline of renal function which can cause severe azotemia and often oliguria or anuria.7 Diabetic nephropathy (DN) is one of the most common and serious microvascular disease in the kidney glomerulus caused by diabetes and adrenal cortex. At present, modern medicine mainly adjusts the acid-base balance, supplementing electrolytes, transfusion, and correcting anemia until the adoption of peritoneal dialysis and hemodialysis for CRF, AKI, and DN treatment.8,9 However, the mortality and morbidity of patients have not appreciably improved during the past four decades. Therefore, the search for new treatments and therapeutic drugs for these diseases is imminent. Clinical studies show that fucoidan extracted from Saccharina japonica reduces urea and creatinine contents and improves renal function in chronic renal failure.10 Based on the clinical efficacy, fucoidan became a treatment for renal disease and was approved by the Chinese Food and Drug Administration in 2003. The medicine’s trade name is Haikun Shenxi Capsule (HSC), and its effective constituent is fucoidan. At present, the major use of HSC is for the treatment of renal disease.11

2. Preparation and structure of fucoidan Fucoidan is a water-soluble polysaccharide that contains covalently linked sulfate groups. It can be extracted with water, dilute acid, or a calcium chloride solution. It is later precipitated by lead hydroxide, aluminum hydroxide, ethanol, or quaternary ammonium salt cationic surfactant.12 The ethanol fractionation precipitation and chromatography method are used to purify fucoidan.13 Our research group have used different methods, including the acid and hot water methods, to extract fucoidan from Saccharina japonica. Comparing the yield and the chemical composition of fucoidan, we found that the hot water extracting method is more suitable for industrial use.14 Due to the complex chemical composition and high molecular weight of fucoidan, its structural research is progressed slowly. The fucoidan derived from brown algae has a branched chain structure, and the type of monosaccharide and connection of the sulfate group are also complicated.15 In our group the fucoidan is obtained by ethanol precipitation from the hot water extraction of Saccharina japonica. Fucoidan is subsequently divided into three fractions by DEAE-Sepharose FF column chromatography. The three fractions are named galactofucan sulfate, fucoglucronomannan, and fucan sulfate. Galactofucan sulfate is the main component of fucoidan, and its

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structure and activity are most thoroughly studied. We identified the structure of the three fractions by both chemical and spectral analyses. The backbone of galactofucan sulfate is primarily a (1 ! 3)-linked α-L-fucopyranose residue and a few (1 ! 4)-α-L-fucopyranose linkages. The branch points are at C-4 of the 3-linked α-L-fucopyranose residues by the β-D-galactose unites (35%, molar ratio) or at the C-2 of the 3-linked α-L-fucopyranose residues by the no-reducing terminal fucose units (65%, molar ratio). The sulfate groups occupy the position C-4 or C-2, and sometimes C-2, C-4 to fucose residues, and C-3 and/or C-4 to galactose residues16(Fig. 1A). The minor fraction fucoglucronomannan is a much more complicated heteropolysaccharide.7 It is revealed that fucoglucronomannan has a backbone of alternating 4-linked GlcA and 2-linked Man, with the first Man residue from the nonreducing end that is accidentally sulfated at C617 (Fig. 1B). The fucan sulfate fraction is mainly made of fucose and sulfate. The structure of fucan sulfate is considerably simpler than the other two fractions. The backbone of fucan sulfate is alternating (1 ! 3)-linked α-L-fucopyranose residues and (1 ! 4)α-L-fucopyranose linkages. The sulfate groups occupy positions C-2 and C-3, sometimes only C-2 in fucose residues (Fig. 1C).

OH

A O

R2

R1 O O O

OH

O

OH

–

O3S

R1 :

SO3–

OH

HO HO

O3C

–

O3S

O -O

HO – O3S

HO

O OH

OH

OH

O

O O3S

–

SO3

–

–

B

C

OH O

OH O

R2 : OH (35%, molar ratio)

HO HO

HO

O

O O OH

HO

–

O3S

HO

OH

O

SO3–

SO3–

OH O

R2 : –

O3S

OH

OH

R2 : OH (65%, molar ratio)

Fig. 1 The structures of Galactofucan sulfate (A), Fucoglucronomannan (B) and Fucan sulfate (C) present in the fucoidan extracted from Saccharina japonica.

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3. Pharmacology and mechanism of fucoidan 3.1 Chronic renal failure (CRF) CRF refers to the chronic progressive renal parenchymal damage caused by kidney atrophy, failure to maintain basic functions, and symptoms of water, electrolytes, and acid-base imbalance. The main causes are primary glomerulonephritis, chronic pyelonephritis, hypertensive renal arteriosclerosis, diabetic nephropathy, secondary glomerulonephritis, and tubulointerstitial lesions. Kunbu (Laminaria japonica Aresch) is utilized in traditional Chinese medicine for the treatment of hydropsy, a symptom of renal failure. In an assay for a biological substance with renoprotective effects, we demonstrated that fucoidan is the active component for hydropsy and may act in several ways to protect against kidney damage. We used two different animal models (subtotal nephrectomy CRF and cryoinjury induced CRF) to test the effects of fucoidan on chronic renal failure.18 In both CRF models, the fucoidan treatment significantly decreases the elevated serum creatinine and serum urea nitrogen levels, and attenuates the histological changes in a dose-dependent manner. In the pathological assay, fucoidan decreases the elevated meningeal areas and the infiltration of inflammatory cells and prevented the tubular histopathological changes. Fucoidan, at dose 200 mg/kg, has renoprotective effects that are similar to dexamethasone at dose 0.07 mg/kg. The activity of fucoidan depends on several structural parameters such as the monosaccharide compositions, the degree of sulfation, the positions of sulfates, the molecular weight, other substitution groups and position, and the glycosidic branching.19,20 Evidence indicated that the chemical modifications of fucoidan may be a means of obtaining new agents, with potential uses in medicine. Our previous study compared the effect of the fucoidan fractions DF (low molecular weight fucoidan) and UF (Fucoglucronomannan) on adenine-induced chronic kidney disease. DF and UF show a significant protective role in deleting the peroxidative and reducing renal damage in CRF rats. Both samples exhibit nearly the same effect on the SUN (Serum urea nitrogen) and SCR (Serum creatinine) levels. However, DF showed a greater effect on the activity/level of CAT, GSH-PX, GSH, and MDA in the serum and liver compared to UF. The mechanism of DF and UF on CKD rats is related to their antioxidant activities, and the samples that enhance the activity of the antioxidant enzymes and reduce the LPO level. All these effects alleviate

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the symptoms of CKD complications.21,22 We also studied the relationship between the molecular weight and the effect of fucoidan on CRF. Low molecular weight fucoidan (Mw 7000–14,000 Da) is more effective in treating chronic renal failure than fucoidan. It also has lower side effects. Thus, the low molecular weight fucoidan has a strong potential for new drug development. Renal fibrosis is a pathogenesis of chronic kidney disease (CKD) that develops into end stage renal disease (ESRD). In the process of fibrosis, the kidney cells are the source of fibrosis factors, growth factors, and the cell phenotype transformation, which ultimately leads to fibrosis. In addition, an imbalance in the production and degradation of the extracellular matrix (ECM) components further promotes renal fibrosis. Shang et al. found that fucoidan significantly inhibits Human Renal Interstitial Fibroblasts (HRIF) proliferation and HRIF secretion of glycoproteins fibronectin (FN). It is speculated that the synthesis of the ECM components is significantly reduced. The reduced ECM improves the kidney function and delays the development of kidney diseases.23 Liu et al. found that in the early and middle stages of CKD, fucoidan inhibits the expression of the cytokines TGF-β1 and MCP-1, thereby delays the progression of renal interstitial fibrosis.24 Our study found that low-molecular-weight fucoidan (LMWF) and its fractions F0.5 and F1.0 influence renal fibrosis in a cell model. HK-2 cell epithelial–mesenchymal transition (EMT) is induced by TGF-β1 or FGF-2, and the cells has a significant fibrosis morphology. LMWF, F0.5 and F1.0 significantly reduce the expression of fibronectin (Fn) and α-smooth muscle protein (α-SMA) in the HK-2 cells at both the protein and gene levels, which are EMT markers. F0.5 and F1.0 also show a significant anti-renal fibrosis effect. The LMWF, F0.5 and F1.0 indirectly regulate the expression of the intracellular glycoprotein SDC-1 and decrease the expression of matrix metalloproteinase-9 (MMP-9) by decreasing the expression of heparanase (HPSE) to reduce fibrosis symptoms.25 Tubulointerstitial fibrosis is recognized as a key determinant of progressive chronic kidney disease (CKD). Cheng et al. evaluated the inhibitory effect of oligo-fucoidan (800 Da) on renal tubulointerstitial fibrosis. They revealed that oligo-fucoidan improves renal function at a dose less than 100 mg/kg/d and reduce renal tubulointerstitial fibrosis in CKD mice. Oligo-fucoidan also inhibits the pressure-induced fibrotic responses and the expression of CD44, β-catenin, and TGF-β in rat renal tubular cells (NRK-52E).26

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Glomerular sclerosis (GS) is a complex process, in which a variety of biologically active substances and various cellular components participate. The environment of the kidney and the body system affect GS occurrence and development. The causes of GS are roughly classified into three types: glomerular hypertension, immunity, and metabolism. Extracellular matrixproducing cells, hemodynamic changes, angiotensin II, endothelin, cytokines, an unbalanced transformation of extracellular matrix, dyslipidemia, oxidative stress, and apoptosis all affect the glomerulosclerosis factor. Wang et al. studied the protective effect of fucoidan in an Adriamycin nephropathy rat model. Their results showed that fucoidan reduces urinary protein, serum creatinine, and urea nitrogen levels; and improves kidney function in the rats with Adriamycin nephropathy and renal cirrhosis. Fucoidan also inhibits the expression of TGF-β1 in the rat kidney, reduces the synthesis of type IV collagen and fibronectin in the extracellular matrix, reduces the expression of TGF-β1, mRNA and PAI-1 mRNA in the renal cortex, and delayed kidney hardening.27

3.2 Acute kidney injury (AKI) Acute renal failure (ARF) is defined when kidney function declines suddenly. The increase in the concentrations of serum creatinine and urea reflects the inability of the kidney to regulate the acid-electrolyte balance and a failure to excrete fluids and waste products. We studied the effect of LMWF and its fractions in an AKI model, which is induced by a 50% glycerol hindlimb injection. LMWF and its fractions, F0.5 and F1.0, were administered through an intraperitoneal injection. The F1.0 fraction significantly reduces the BUN, SCr levels, and kidney weight. The body weight is maintained at the normal level, and the blood glucose level is the same as that in the normal group. These results indicate that the F1.0 fraction is effective in the treatment of AKI. The pathogenesis of AKI is currently recognized as vasoconstrictive, oxidative stress, apoptosis, inflammatory stimuli, and ischemia-reperfusion injury (IRI). Aging, a previous medical history (chronic renal insufficiency, heart disease, diabetes), and rhabdomyolysis are all potential factors that affect AKI. Glycerol-induced AKI rats experience rhabdomyolysis which, in turn, exacerbates renal oxidative stress and the endoplasmic reticulum stress (ER) in rats.28 Nara et al. studied short-term glycerol-induced changes in inflammation and lipid peroxidation in the rat AKI model. Their results suggest that pro-inflammatory cytokine-mediated inflammatory responses

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might cause rhabdomyolysis soon after the glycerin injection, which is exacerbated by lipid peroxidation.29 We studied the effect of LMWF in HK-2 cells, and the results showed that LMWF inhibits the apoptotic pathway by reducing the activity of the MAPK pathway in a dose-dependent manner.25

3.3 Diabetic nephropathy (DN) Diabetic nephropathy (DN) is one of the most common and very serious chronic complications of microvascular disease. It is the leading cause of end-stage renal failure. The early stage of DN is characterized by renal hypertrophy, glomerular hypertrophy, glomerular hyperfiltration, and microalbuminuria.30 As a result of increased intracapillary pressure and endothelial cell dysfunction, retinal capillaries show an increased leakage of fluorescein, and the glomerular capillaries have elevated albumin excretion rates.31 Our previous study revealed that fucoidan has a protective effect on streptozotocin-induced DN in rats. The fucoidan treatment group not only decrease the level of blood glucose, blood urea nitrogen, and creatinine compared with the DN group, but also significantly increase the level of albumin, serum insulin, and β2-microglobulin. In addition, the fucoidan treatment group show an improvement in renal morphometry. From these results, we concluded that fucoidan improves the metabolic abnormalities in DN rats and delays the progression of diabetic renal complications.32 Oxidative stress and the inflammasome are the main intrinsic DN pathogenic factors. The treatment of DN mainly inhibits inflammation and reduces oxidative stress. Hu et al. studied the renoprotective effects of fucoidan from Acaudina molpadioides (Am-FUC) in type 2 diabetic mice induced by an intraperitoneal administration of streptozotocin and a high-fat diet. Their results showed that Am-FUC attenuates renal dysfunction by decreasing urinary urea nitrogen, albumin, beta-N-Acetyl-D-glucosaminidase, and the albumin-tocreatinine ratio. Am-FUC has a significant renoprotective effect by attenuating the TGF-beta 1 signaling, which is associated with an improvement against hyperglycemia, obesity, oxidative stress, and inflammation.33 We also studied the effect and mechanism of LMWF on streptozotocin-induced DN rats. The experimental results showed that LMWF prevents weight loss in the DN rats. It also significantly reduces the level of biochemical markers in the blood and urine samples, and reduces the level of hyaluronic acid (HA) and advanced glycation end product receptor (AGER) levels in the DN rats. LMWF maintains the glomerular basement membrane (GBM)

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and glomerular structural integrity, improves the glomerular filtration function, protects glycosaminoglycans from abnormal degradation, and prevents the production and accumulation of advanced glycation end products (AGE). It also reduces the inflammatory response in DN rats.34 Furthermore, we also found that LMWF is superior to captopril in reducing P-selectin expression at both mRNA and protein levels. Our data demonstrates that P-selectin modulates inflammation in the kidneys of DN rats, especially in the glomerulus, injures the GBM, and produces other abnormalities. However, LMWF ameliorates DN development and progression by inhibiting P-selectin and selectin-dependent inflammation.35 We also studied the effect of fucoidan in NRK-52E cells induced by high glucose. We found that fucoidan inhibits the expression of PKC-α and PKC-β and significantly downregulated the protein expression. In fucoidan-treated cells, TGF-β1 expression is also affected. The results indicated that fucoidan regulates high glucose-induced diabetic nephropathy through the PKC and TGF-β signaling pathways.

4. Clinical uses and efficacy of fucoidan After two phases of clinical trials, Haikun Shenxi Capsule (HSC, the main active component is fucoidan) was received a New Drug Certificate as a traditional Chinese medicine in 2003 from the Chinese Food and Drug Administration (SFDA). The medicine is produced in Huinan Changlong Co. Ltd., Jilin, China. At present, this medicine is widely used for the treatment of chronic renal failure in China. HSC is taken orally; two capsules three times a day, as recommended by the SFDA. A total of 137 pharmacology and clinical research papers related to HSC were published in 2006–2018 based on the CNKI (China National Knowledge Infrastructure), VIP (Chongqing VIP Chinese Scientific Journals Database), and Wan Fang database searches. A total of 134 papers clearly demonstrated the effects of HSC on the clinical control of renal insufficiency and diabetic nephropathy. For the efficacy determination, according to the efficacy standard of the “Guidelines for Clinical Research of New Drugs in Traditional Chinese Medicine” formulated by the Ministry of Health, the serum creatinine (sCr) and creatinine clearance (cCr) should be evaluated before and after treatment. If the cCr increase ratio exceeds 20% or the sCr decrease is more than 20%, it is markedly effective. A cCr increase of more than 10% or a sCr decrease of more than 10% is effective, and no significant change before and after treatment is ineffective. Ten papers reported 349 cases where all

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60

marked effective

effective

ineffective

50

Rate %

40

30

20

10

0

Treatment group

Control group

Fig. 2 Treatment efficacy of of HSC alone on chronic renal failure.

patients suffering chronic renal failure (CRF) that used HSC alone as treatment group, 182 cases are markedly effective, 152 (the numbers did not add up) cases are effective, with a total effective rate of 96.83%. In contrast, the 349 cases in the control group where all patients suffering CRF received the routine treatment, 113 cases are markedly effective and 138 cases are effective, with a total effective rate of 71.91% (Fig. 2).36–45 Forty papers reported using the combination of HSC and other therapeutic drugs to treat chronic renal failure (CRF). There were 1781 cases in the treatment group, and the patients in the treatment received HSC plus a salviae mihiorrhizae composite injection or a Ligustrazine Hydrochloride Injection, or compound -Ketoacid tables, or Shenshuaining tables, or a Shenkang injection. A total of 730 cases are markedly effective and 814 cases are effective, with a total effective rate of 86.69%. Out of the 1661 cases in the control group, where patients received the routine treatment, 657 cases are effective, with an overall treatment efficacy of 65.20% (Fig. 3).46–85 Thus, the total effective rate of the HSCs, whether used alone or in combination with other drugs, is approximately 86.88%, while in the control group it is approximately 65.04%. The treatment group have an average that is 22% higher than the control group, which means the curative effect is significant. Four other papers reported that the HSCs were used to treat diabetic nephropathy. Of the 242 cases where patients suffering diabetic nephropathy who were treated with HSC alone, 141 cases are markedly effective and

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50

marked effective

effective

ineffective

45 40

Rate %

35 30 25 20 15 10 5 0

Treatment group

Control group

Fig. 3 Treatment efficacy of HSC combined with other medicines on chronic renal failure. 70

marked effective

effective

ineffective

60

Rate %

50 40 30 20 10 0 Treatment group

Control group

Fig. 4 Treatment efficacy of the HSC alone on diabetic nephropathy.

71 cases are effective, with a total effective rate of 90.08%. Out of the 170 cases in the control group, where patients received the routine treatment, 100 cases are markedly effective and 70 cases are effective, with a total effective rate of 70.25% (Fig. 4).86,87 Four papers reported that the HSCs were used to treat diabetic nephropathy with other medicines. Out of 191 cases of diabetic nephropathy that were treated with the HS, 115 cases are marked effective and 58 cases are effective, with a total effective rate of 90.59%. Out of 159 cases

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70 marked effective

effective

ineffective

60

Rate %

50 40 30 20 10 0 Treatment group

Control group

Fig. 5 Treatment efficacy of HSC combined with other medicines on diabetic nephropathy.

in the control group, where patients received the routine treatment, 72 cases are markedly effective and 55 cases are effective, with a total effective rate of 79.87% (Fig. 5).88–91 These clinical cases indicated that HSC improves the clinical symptoms of patients with chronic renal disease, significantly improves renal function, and has no obvious adverse side effects. Thus, HSC has good therapeutic effects on patients suffering chronic renal insufficiency and diabetic nephropathy.

5. Future perspectives The impressive clinical efficacy of HSC on CRF and DN diseases indicates that fucoidan is a useful and important sulfated polysaccharide that can be used to treat kidney diseases. Recently, the capsule’s structure and bioactivities are studied widely. However, the pharmacokinetics of fucoidan have not been thoroughly elucidated to date. Thus, developing new methods and novel assays to perform reliable pharmacokinetic studies on fucoidan is necessary to for clinical use.

Acknowledgments This study was supported by the Youth Innovation Promotion Association of CAS, under grant No. 2016190, the Science and Technology project of Fujian Province (No. 2017T3015), Jiangsu Science and Technology Program (BE2015335), the Jiangsu Innovation Entrepreneurs Talent Program, and the Natural Science Foundation of China (NSFC) (41376166).

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