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Review ArticleReview of Herbal Traditional Chinese Medicine forthe Treatment of Diabetic Nephropathy

Guang-dong Sun, Chao-yuan Li, Wen-peng Cui, Qiao-yan Guo, Chang-qing Dong,

Hong-bin Zou, Shu-jun Liu, Wen-peng Dong, and Li-ning Miao

Department of Nephrology, Second Hospital of Jilin University, Changchun , China

Correspondence should be addressed to Guang-dong Sun; [email protected] and Li-ning Miao; [email protected]

Received May ; Accepted July

Academic Editor: David W. Powell

Copyright Guang-dong Sun et al. Tis is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Diabetic nephropathy (DN) is the most serious chronic complications o diabetes; % o diabetic patients develop into endstage renal disease (ESRD). However, exact pathogenesis o DN is not ully clear and we have great difficulties in curing DN;poor treatment o DN led to high chances o mortality worldwide. A lot o western medicines such as ACEI and ARB have beendemonstrated to protect renal unction o DN but are not enough to delay or retard the progression o DN; thereore, exploringexact and easible drug is current research hotspot in medicine. raditional Chinese medicine (CM) has been widely used to treatand control diabetes and its complications such as DN in a lot o scientic researches, which will give insights into the mechanism

o DN, but they are not enough to reveal all the details. In this paper, we summarize the applications o herbal CM preparations,single herbal CM, and/ormonomers rom herbal CMin thetreatment o DN in therecent years, depictingthe renal protectiveeffectsand thecorresponding mechanism, through which we shed light onthe renal protectiveroles oCM in DN with a particularocus on the molecular basis o the effect and provide a benecial supplement to the drug therapy or DN.

1. Introduction

Diabetic nephropathy (DN) is a widely recognized microvas-cular complication o diabetes andalmost the leading cause oend-stage kidney ailure worldwide responsible or morbidityand mortality []. Clinical maniestations o DN includeinitial increase in glomerular ltration (GFR), proteinuria,

increased creatinine levels, and eventually decreased GFR []. Major pathological changes o DN are virtually indistin-guishablein both type andtype diabetes,including mesan-gial expansion, extracellular matrix (ECM) accumulations,tubulointerstitial brosis, and glomerular sclerosis. Hyalinearteriolosclerosis is ofen prominent in the established DNpathological eatures caused by endothelial dysunction andinammation [].

Multiple actors have been implicated in the pathogenesiso DN including hyperglycemia induced activation oadvanced glycation end products (AGEs) and reactive oxygenspecies (ROS); JAK-SA pathways and G protein signaling;activation o the PKC, renin-angiotensin aldosterone system

(RAAS), transorming growth actor -Smad-mitogen-activated protein kinase (GF--Smad-MAPK), deregulatedexpression o cyclin dependent kinases (CDK), and theirinhibitors; and aberrant expression o ECM proteins, ECM-degrading enzymes, metalloproteinases, and their inhibitors[]. Te abovementioned actors can induce aberrant expres-sion o probrotic and proinammatory cytokines, cell-cycle

genes, and ECM genes involved in DN []. A large number onovel treatment options has arisen rom experimental studiesbased on the pathogenic actors o DN, including intensiveglycemic control, precise blood pressure control, optimalRAAS blockade with ACEI/ARB, lie style modications suchas exercise and dietary restrictions, and a lot o novel agents[], but the portion o ESRD due to DN still remains high inspite o the widespread application o numerous therapeuticapproaches ocusing on the management o actorsmentioned above []. Tereore, interventions that couldeffectively delay the progression o DN are greatly required.

In China, traditional Chinese medicine (CM) has beenwidely used in the treatment o diabetes andits complications

Hindawi Publishing CorporationJournal of Diabetes ResearchVolume 2016, Article ID 5749857, 18 pageshttp://dx.doi.org/10.1155/2016/5749857
http://dx.doi.org/10.1155/2016/5749857http://dx.doi.org/10.1155/2016/5749857


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Journal o Diabetes Research

or a long time []; CM has lots o advantages over the con-ventional medical approaches in the prevention o diabeticcomplications because o less toxicity and/or side effects []. In this review, we will explore the advance o herbalCM treatment on DN in recent years, based on theexperimental and clinical studies to note the scientic basis

or the therapeutic effects o CM on DN.

2. Applications of TCM in DN

Plants have been widely used or medical purposes longbeore recorded history []. In China, CM emerged andinuenced the surrounding countries such as Japan andSouth Korea; increasing popularity o CM caused greatinterests in laboratory and clinical investigations in lots odiseases on its efficiency and action mechanism. CM mani-ests as herbal medicine, acupuncture, moxibustion, massage,dietary therapy, and physical exercise including shadowboxing and Qigong, and herbal remedies are the ocus oCM in mainland China [] and acupuncture is prevalentin the United States []. Under the urgent need or thetreatment o DN,we ocus on theupdate o theefficient herbalCM preparations, single herbal CM, and/or monomersrom herbal CM in DN related clinical and experimentaltrials, through which we explore the effective herbal CMor DN and clearly put orward underlying mechanism in thetreatment o DN.

.. CM Preparations in DN. CM preparations are appliedas decoction, pill, and capsule in the treatment o DN. Wewill introduce the CM preparations in alphabetical orderabout components o CM preparations, therapeutic effectsin clinical or experimental studies, and relevant mechanism.

All the mentioned CM preparations in this review are listedin able .

... Chaihuang Yishen Granule (CHYS). Chaihuang Yishengranule (CHYS, also called Qilong-Lishui granule) is com-posed o radix astragali,Dioscorea nipponica, radix bupleuri,

Angelica sinensis, Pyrrosia petiolosa, Polyporus umbellatus,andHirudo nipponica. A recent study in SZ plus uninep-hrectomized induced rats showed that CHYS could be a ther-apeutic agent or DN by blocking GF-/Smad-mediatedrenal brosis [].

... Compound Rhizoma Coptidis Capsule (CRCC). Com-

pound rhizoma coptidis capsule (CRCC) is composed orhizoma coptidis,Kudzu root,dwar lilytur,and Loquat lea.CRCC has been shown to protect renal unction and slowdown the progression o DN by the suppression o GF-and type IV collagen expression in SZ induced diabetic rats[].

... CompoundShenhua ablet (CS). Compound Shenhuaablet (CS), is composed o radix astragali, ructus ligustrilucidi, rhizomazedoaria, and honeysuckle. CS treatment inSZ induced diabetic rats showed that urine mAlb, Scr, BUN,Glu, G, and C were signicantly lower than the diabeticmodel group [].

... Danggui Buxue ang (DB). Danggui buxue tang(DB), a preparation including radix astragaliandradix

Angelica sinensis, has been shown to partially attenuate theincreases in blood glucose, G, and CHO, and DB wassupposed to retard DN progression by suppressing GF- expression in SZ induced diabetic rats []. In the HG

stimulated glomerular mesangial cells, DB could inhibitcell prolieration and expression o LN, FN, and collagen IVindicating the renoprotective effect o DBon DN at the earlystages [].

... Danggui Shaoyao San (DSS). Danggui Shaoyao San(DSS) is a amous CM ormula comprising six herbalmedicines: radix Paeoniae Alba, radix Angelica sinensis, rhi-zoma Chuanxiong,Poria cocos, rhizomaAtractylodis macro-cephala, and rhizoma Alismatis. DSS has been shown toprotect renal unction in SZ induced diabetic rats throughregulating plasma glucose and attenuating AGEs expressionin diabetic glomeruli [].

... Fufang Xue Shuan ong (FXS). Fuang Xue Shuanong (FXS) capsule is composed o radix notoginseng,Salvia miltiorrhiza, XuanShen, and radix astragali and hasbeen used to treat DN or many years. High dose o FXStreatment could prevent glomerular hypertrophy and mesan-gial matrix expansion through regulation o oxidative stressincluding increasing SOD activities and decreasing MDAlevels in the kidney o HFD-ed plus SZ induced rats [].

... Hachimijiogan (HJG). A most popular herbal medicinein Japanese Kampo, Hachimijiogan (HJG, Ba Wei Di HuangWan in Chinese), is extracted rom a mixture oRehmanniaradix, corni ructus, Dioscorea rhizome, Hoelen, Alismatisrhizome, Moutan cortex, Cinnamomi cortex, and Aconitituber. In subtotal nephrectomy plus SZ induced rats, HJGcould reduce blood glucose and urinary protein excretionlevels and increase Ccr; urthermore, HJG could ameliorateoxidative stress and AGEs ormation associated with DNand subsequently prevent the development o renal lesionsincluding glomerular sclerosis, tubulointerstitial lesions,mesangial expansions, and atherosclerosis []. In sponta-neous diabetic WBN/Kob rats with DN, HJG could preventDN progression through several established biomarkers inplasma [] and by reducing renal oxidative injury andexpression o FN and GF- proteins []. In OLEFrats, HJG could reduce GF-, FN, iNOS, and COX-

expressions in kidney cortex, urinary protein excretion wasdecreased, Ccr levels were improved, and serum glycosylatedprotein and AGEs were reduced effectively; data mentionedabove suggested that HJG has benecial effect on the DNprogression [].

... Hu-Lu-Ba-Wan (HLBW). Hu-Lu-Ba-Wan (HLBW),composed origonella foenum-graecumL. (FG) and Pso-ralea corylifoliaL. (PC), has been shown to improve hyper-glycemia, hyperlipidemia, and proteinuria in the HFD-edplus SZ induced rats and could play renoprotective effectin attenuating renal oxidative stress via PKC-/NADPHoxidative pathway [].


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:Continued.

Name

Origins

Methods

Results

Pathways

Oryeongsan

Poria,A

lismatisrhizoma,Polyporus

umbellatus(Pers.)Fries,rhizoma

Atractylodismacrocephala,and

RamulusCinnamomiCassiae

Typediabeticanimalstudy(SZ

inducedrats)

Decreasingplasmaglucose,UAER,and

Ccr,attenuatingmesangialmatrix

expansion,anddownregulatingincreased

NF-B,GF-expressio

n,elevated

AGEs,andFNaccumulation

Troughattenuating

increasedNF-B

andGF-expression[]

Typediabeticanimalstudy(db/db

mice)

DecreasingCandG,improvingblood

glucose,insulin,glucosetolerance,and

HOMA-IR,Ccr,urinealbumin,and

BUN,andreducingGF-,Smad/,

collagenIV,CGF,and

IMP

TroughdisturbingtheGF-/Smads

pathway[]

QJC

Radixastragali,Hirudo,Rehmannia

root,andrhizomaPolygonati

Humanstudy(DNpatients)

DecreasingSBPandDBS

,increasing

ALB,andslowingdowntheincreaseof

ScranddecreaseofeGFR

[]

QWG

Radixastragali,radixRehmanniae,

Euonymusalatus,andRhubarb

Typediabeticanimalstudy(KK-Ay

mice)

Alleviaterenalpathologicalchangesand

decreasingGF-expre

ssion

Troughinhibiting

GF-expression

[]

SKW

Radixastragali,HerbaLeonuri

Typediabeticanimals

tudy(SZ

inducedrats)

Protectingrenalfunction

TroughincreasingN

Oanddecreasing

GF-excretion;aff

ectingpodocytes

specialproteinsexpression[]

Typediabeticanimals

tudy(SZ

inducedrats)

Alleviatingmorphologicaldamageof

kidney

TroughreducingAngIIinplasmaand

kidneyandinhibitingrenalA(1)R[]

Cellularstudy(mesangialcells)

SuppressingFNsecretion

TroughGF-way[]

SQABC

RadixastragaliandSalviamiltiorrhiza

Typediabeticanimalstudy(SZ

inducedrats)

ReducinghUPexcretionand

improvingreabsorptionfunction

Troughenhancinga

ntioxidativeactivity

andupregulatingmegalin[,]

Cellularstudy(NRK-Ecells)

ProtectingHGinjuredNRK-Ecellsand

improvingproteinuptake

SF

Astragalus,rawRehmann

iaroot,

sanchiroot,euonymusb

ranchlet,

rhubarb,bitterorange,anddogwood

fruit


Regulatingandimprovin

gphospholipids

metabolism

DecreasinginvivoCys,H

cy,SAM,and

SAH

TroughinhibitingP

KCpathwayand

reducingphospholipidsmetabolism;

improvinginvivohypomethylationand

oxidativestress[,

]


mice)

UpregulatingJAK,JAK

,andSAand

downregulatingSA

RegulatingtheJAK/S

A/SOCSpathway

[]

SL

Radixastragali,radixRehmannia,

leech,bilesouthstar,Artemisia

anomala,andZelan

Typediabeticanimalstudy(SZ+

nephrectomizedrat)

DecreasingECMcomponents

Troughdownregula

tingGF-and

IMP-andupregulatingMMP-

expression[]


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mice and HG stimulated RMC, which was mediated throughdecreasing oxidative stress and productions o GF-, FN,and collagen IV in renal cortex during the development oDN [].

... Xiaoke Granule (XKG). Xiaoke granule (XKG, Xiaoke

Keli in Chinese) includes our crude drugs: radix astragali,MountainCornus, leech, and winged euonymus twig. It wasreported that XKG could decrease asting blood pressure and h urinary protein excretion in the / nephrectomy andSZ induced diabetic rats groups []. In the subsequentmechanism study, XKG was proved to exert renal protectiveeffect in DN through downregulating GF- expression inrat mesangial cells [].

... Xiexin Decoction (XXD). Xiexin decoction (XXD) iscomposed o three crude drugs including radix et rhizomarhei, rhizoma coptidis, and radix Scutellaria and has beenused orthe treatmento DM orat least years.One studyin HFD-ed plus SZ induced rats showed that XXD couldattenuate albuminuria and renal pathologicalchanges, reduceAGEs, inhibit RAGE and inammation actors expression,suppress NF-B, and downregulate renal GF-. All thesedata suggested that renal protective potential o XXD wasinvolved in inhibition o inammation through downregulat-ing NF-B pathway, reducing renal AGEs and RAGE in dia-betic rats []. A recent study o XXD components in db/dbmice showed thatmulticomponent herbaltherapeutic ormu-lations could be a useul approach or the treatment o DNthrough reducing the expression o NF-B and GF- [].

... Xianzhen ablet (XZ). Xianzhen tablet (XZ, a Chi-nese patent compound recipe), is composed o astragali radix,radixRehmannia, ructus ligustri lucidi,Scutellaria baicalen-sisGeorgi, rhizoma coptidis, dodder weed, airy spleen, andSalvia miltiorrhiza. XZ was reported to decrease bloodglucose and HbAc in diabetic rats, improve renal unction,ameliorate proteinuria, and reduce glomerular extracellularmatrix expansion and thickness o basement membrane,which was mediated by the inhibition o AGEs accumulationand RAGE mRNA levels in the kidney cortex o SZ induceddiabetic rats [].

... Zhibai Dihuang Pill (ZDP). Zhibai Dihuang Pill (ZDP)is one o the CM preparations, composed o rhizoma ane-marrhenae, cortex phellodendri, radixRehmanniapreparata,

rhizoma Dioscorea, ructus corni, cortex Moutan, rhizomaAlismatis, andPoria. ZDP has been revealed to have protec-tive effects in experimental DN animal models and DNpatients. In a recent metabonomic analysis o ZDP in thetreatment o SZinduced diabetic rats, ZDPcould ameliorateDN by intervening in some dominant metabolic pathwayssuch as inhibiting glucose and lipid metabolism and enhanc-ing methylamine metabolism [].

... Zao Huang Mixture (ZHM). Zao Huang Mixture(ZHM) is composed o extracts oSargassum and rhizomarhei. One study has shown that ZHM could prevent theprocess o DN by decreasing the expression o GF-

and type IV collagen in HG stimulated human glomerularmesangial cells [].

... Zhenqing Recipe (ZQR). Zhenqing Recipe (ZQR), aChinese herbal prescription composed o crude drugs: ruc-tus ligustri lucidi, Eclipta prostrate, and Dioscorea opposite,

has been used to improve renal unction o DN patients.In the study or the underlying mechanism, ZQR has beenshown to inhibit the overexpression o GF- and FN in therenal cortex o HFD-ed plus SZ induced diabetic rats; itsrenoprotective effect was mediated by inhibiting SREBP-coverexpression and its target genes including ACC and FAS[].

... Zishentongluo (ZSL). Zishentongluo (ZSL) is com-posed o eleven Chinese herbs: raw Astragalus, Angelica,safflower, zedoary turmeric, Dodder, radixRehmannia, dog-wood,Poria,Epimedium, earthworm, and Schisandra. ZSLhas been shown to be superior to benazepril in improving themetabolic and renal unction in DN patients at early stagepartially by modiying ANP, VEGF, and E- expressions[].

.. Monomers/Single CM in DN. With the developmento modernization o CM preparations and applications inthe treatment o DN, pharmacological complexity is difficultto be distinguished or the precise underlying mechanism,and, to avoid the toxicity and side effects, there is anincreasing interest o single herbal CM and/or monomersrom herbal CM in the treatment o DN, and they are moreappropriate than CM preparations to clariy the preciseaction mechanism on DN. All the single herbal CM andmonomers are listed in able .

... Astragalus/Radix Astragali. Astragalus (Huang Qi inChinese), also named as radix astragali, is a CM romMongolian milkvetch or membranaceusmilkvetch. A meta-analysis comprising studies showed that Astragalusinjec-tion had more therapeutic effect in DN patients such asdecreasing BUN, Scr, and urine protein and improving Ccrand serum albumin level [], and rebalancing GF-/Smadsignaling could be a potential mechanism to prevent DNin KK-Ay mice []. Astragalus may protect diabetic ratskidney mediated by downregulation o ie- [], and radixastragali was reported to upregulate c-met expression inhuman kidney broblasts to delay the progression o DN

[].wo majorisoavonoidsin radixastragali,calycosin andcalycosin--O-beta-D-glucoside, could inhibit HG inducedmesangial cell early prolieration and AGEs-mediated cellapoptosis, suggesting these two isoavonoids have thera-peutic potential to prevent the progression o DN []. Arecent review showed that total polysaccharides, avonoidsractions, saponins, and several isolated compounds haveantidiabetic potentials, which throw light upon urther inves-tigations that should be conducted on the treatment oDN and relevant underlying mechanism []. AstragalosideIV (ASI) in radix astragali is considered to be an activeconstituents; ASI could inhibit human tubular epithelial cellsapoptosis and reduce GF- expression, suggesting a new


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:Continued.

Name

Origins

Methods

Results

Pathways

Skimmin

Hydrangeapaniculata

Typediabeticanimalstudy(SZin

ducedrats)

DecreasingScrandblood

glucoselevel,

alleviatingglomerularseg

mentalsclerosisand

tubularvacuolardegeneration,and

downregulatingGF-a

ndGF-receptorI

expression

TroughinhibitingGF-

pathway[]

SM

Salviamiltiorrhiza


ducedrats)

DecreasingGF-,CG

F,PAI-,FNED-,

collagenIV,andRAGEov

erexpressionand

protectingtubularfunctio

nandstructure

TroughinhibitingGF-

pathway,oxidativestress,and

inammation[]

GP

PaeonialactioraPall.


ducedrats)

Elevatingantioxidantenzymeanddecreasing

p-pMAPKandNF-B

DecreasingScr,BUN,and

hUPand

improvingrenalhistopath

ology

Troughinhibitingoxidativestress

[]

Typediabeticanimalstudy(HFD+SZ

inducedrats)

Troughinhibiting

Wnt/beta-caten

insignalingpathway

[]

MP

Ligusticumchuanxiong


ducedrats)

Improvingrenalfunction

TroughdownregulatingVEGF

expression[]

riptolide

Diterpenepuriedfrom

wHF


mice)

Decreasingalbuminuria,alleviatingglomerular

hypertrophyandpodocyt

einjury,and

attenuatinginammation

andoxidativestress

inkidney

Troughinhibitinginammation

anddyslipidemia[]

wHF


Preventingpodocyteinjury

DownregulatingGF-,OPN,and

CGF[]

VOMBP

MagnoliabiondiiPamp.


ducedrats)

DecreasingUmAlb,sP-selectininserum,

andP-selectininrenaltissue

InhibitingP-selectin[]


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treatment or DN probably mediated by the inhibition o pMAPK pathway activation and HGF overproduction [].

... Berberine (BBR). Berberine (BBR), an effective com-pound o herbal CM, includes Coptis chinensis, HydrastisCanadensis, Berberis aristata, Berberis aquifolium,andArcan-

gelisia ava.BBR treatment could restore renal unctional parameters,

improve glucose and lipid metabolism disorders, suppressalterations o histological and ultrastructural changes in kid-ney, and increase cAMP levels in HFD-ed plus SZ induceddiabetic rats, and the renal protective effect is exerted bymodulating the G protein-coupled receptor kinases (GRKs)in G protein-AC-cAMP signaling pathway []. A previousstudy showed that BBR-containing CM could increaseglucose uptake and lipid oxidation with insulin sensitivity inZucker diabetic atty rats [].

... CLL/Curcumin. Curcuma longa L. (CLL) has been

widely used to prevent diabetic vascular complications inrecent years. Curcumin and demethoxycurcumin are isolatedrom CLL and have been shown to potentially protect DN byreducing AGE-induced oxidative stress and restoring AGE-induced mesangial cell apoptosis []. In the treatment oDN in db/db mice, curcumin has been shown to decreasealbuminuria and attenuate glomerular sclerosis by inhibitingphosphorylation o SA and degradation o IB []. Asystemic review and meta-analysis o ourteen randomizedcontrolled trials suggested that curcumin has protectivepotentials on the kidneys o diabetic rats/mice [].

... -Dodecyl--methoxycyclohexa-,-diene-,-dione

(DMDD). -Dodecyl--methoxycyclohexa-,-diene-,-dione (DMDD), isolated rom the tuberous roots o A.carambolaL. (Oxalidaceae), has been shown to enhance thereduced SOD activities in the kidney o KK-Ay mice andinhibit the progression o DN through decreasing AGEs andGF- levels [].

... Dracorhodin Perchlorate (DP). Dracorhodin perchlo-rate (DP), one o the main compositions o Dragons blood,has been shown to prevent and retard renal brosis o DNpartially through inhibiting SGK and FN expression inhuman mesangial cells [].

... EGB. Ginkgo biloba extract (EGB), taken rom theleaves o Ginkgo biloba, is a mixture containing avonoidglycosides and has been proven to ameliorate hemodynam-ics, suppress PAF and ACE activities, scavenge ROS, relax

vascular smooth muscles, and suppress AGEs expression. Ina previous study on DN patients, EGB treatment has beenshown to decrease urinary mALB, -MG, IgG, F, RBP, andNAG in DN patients compared with control group, whichsuggested that EGB has renoprotective effect on the earlyDN []. Te subsequent mechanism study showed that EGBcould suppress rat mesangial cells hypertrophy and ECMaccumulation through decreasing Smad/ and GF- andincreasing Smad [], while in DN patients EGB has been

proven to retard early DN development through decreasingserum sICAM- and sVCAM- levels [].

... Flos Abelmoschus manihot. Flos Abelmoschus manihot(Huangshukuihua in Chinese) has been widely used asthe neuroprotective drug or cerebral ischemic reperusion

injury. otal avone glycosides o os A. manihot (FA)contain identied avone glycosides. FA pretreatment hasbeen shown to prevent renal damage and podocyte apoptosisin SZ induced rats []. A meta-analysis o randomizedcontrolled trials showed that os Abelmoschus manihothadsignicant effect on renal unction in the treatment o DNdeserving urther investigation [].

... Genipin. Genipin is a glycone derived rom geniposidepresent in ruit oGardenia jasminoides. Genipin has beenproven to ameliorate body weight loss and urine albuminleakage, attenuate GBM thickness, and restore the podocyteexpression o podocin and W in diabetic mice; the protec-tive effect o Genipin on DN is probably through suppressingthe upregulation o mitochondrial UCP in SZ induceddiabetic mice kidneys [].

... Houttuynia cordata Tunb. (HC). Houttuynia cordataTunb. (HC, Yu Xing Cao in Chinese), pungent in tasteand cool in nature, has been reported to reduce urinaryproteins in the patients with nephrotic syndrome; HC hasalso been shown to protect diabetic kidney unction throughdecreasing the expression o GF- and increasing theexpression o BMP- [].

... Icariin. Icariin is a major constituent o avonoidextracted rom the plant herba epimedii and has been shownto relieve renal damage in SZ induced diabetic rats throughinhibiting the expression o GF- and collagen IV protein[].

... LAB. Lithospermate B (LAB), a tetramer o caffeicacid isolated romSalvia miltiorrhizaradix, was identied asantioxidant and PKC inhibitor in the renoprotective effectsunder diabetic conditions in vivo and in vitro []. In theSZinduced diabetic rats, delayed LAB treatment could inhibitrenal MDA, microalbuminuria, mesangial expansion, andglomerular hypertrophy, and in mesangial cells LAB couldinhibit HG and H

2O

2induced GF- and FN secretion, HG

induced intracellular PKC activation, and ROS generation,

which suggested that LAB could signicantly suppress theprogression o diabetic renal injury. A recent study showedthat LAB could prevent diabetic atherosclerosis by inductiono the Nr-ARE-NQO pathway to inhibit VSMCs proli-eration and migration and vascular damage []. All thesendings suggested that LAB could be a new therapeuticagent in the treatment o DN. In the subsequent study,Salvia miltiorrhiza could protect SZ induced diabetic rats byinhibiting the overexpression o GF-, CGF, PAI-, andFN in renal cortex.

... LBP. Lycium barbarum polysaccharide (LBP) isextracted rom the ruit o goji berry(Solanaceae); LBP


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has been shown to protect SZ induced diabetic kidneyunction via decreasing the activation o ERK/ through theinvolvement o PKC in mesangial cells [].

... LGP. Lyoniresinol alpha-O-beta-D-glucopyranoside(LGP) is isolated romAverrhoa carambolaL. (Oxalidaceae)

root (ACLR), including two chiral lignin glucosides: LGPand LGP. LGP treatment has been shown to decreasehyperglycemia and the expression o related proteins includ-ing NF-B, caspase-, caspase-, caspase-, and Bax in SZinduced diabetic mice. LGP also could alleviate glomerularhypertrophy, excessive ECM accumulation, and glomerularand tubular basement membrane thickness. All these datasuggested that LGP could be a potential therapeutic agentin DN [].

... Ligustrazine. Ligustrazine, a bioactive component oChuangxiong, has been widely used in the treatment o vas-cular diseases such as myocardial and cerebral inarction inChina. A meta-analysis o studies showedthat Ligustrazinehas therapeutic effect to improve renal unction and reduceurine protein excretion in DN patients []. Further studiesshould be conducted to reveal the underlying mechanism orthe treatment on DN.

... MC. Moutan cortex (MC), the root bark o Paeoniasuffruticosa, has been shown to have the protective effectagainst atherosclerosis and inammation and inhibitoryeffect on the production o ROS. MC was reported toincrease activity o SOD, GSH-PX, and CA and reduceMDA in vitro or in vivo; urthermore, MC could decreaseblood glucose, Scr, and urine protein in HFD-ed plus SZinduced diabetic rats, which suggested that MC has renalprotective effect in AGEs-induced mesangial cell dysunctionthrough attenuating oxidative stress pathway [], while, inAGEs-induced rat mesangial cells, MC could inhibit FNand collagen IV expression in matrix []. Apart rom theabovementioned evidence o renal protective effect on DN,MC could ameliorate activity on the inammation via targeto RAGEin vitroorin vivo[].

... Morroniside. Corni ructus, a constituento HJG, usedas a traditional medicine in China and Japan, has been shownto be superior to aminoguanidine treatment in suppressinghyperglycemia, proteinuria, renal AGE ormation, and GF- expression in SZinduced diabetic rats []. Morroniside,

isolated rom corni ructus, could exhibit protective effectsagainst SZ induced renal damage by inhibiting hyper-glycemia and oxidative stress []. Another study showedthat components o corni ructus could play protective effecton early stage o DN in type diabetic rats mediated bythe regulation o podocytes. Loganin rom corni ructus andits derivatives could inhibit the expression o FN and IL-in the HG stimulated mesangial cells, which supported thetraditional use o corni ructus in DN and relevant kidneydiseases [].

... Panax Notoginoside (PNS). Panax notoginoside (PNS)is extracted rom radix notoginseng and has been shown to

protect kidney in type diabetic rats at early stage throughinhibiting the expression o VEGF protein and enhancingBMP- expression in the kidney []. Another report showedthat the protective effect o PNS in kidney was mediated byinhibiting GF- expression and enhancing the expressiono Smad []. Ginsenoside Rg, an active ingredient isolated

rom PNS, has been shown to improve the renal pathologicalchanges in SZ induced diabetic rats through reducing GF- expression and inammatory reaction actors includingCRP and NF- []. Ginsenoside Rg also could effectivelyrelieve aldosterone-induced oxidative stress through which itindirectly inhibits aldosterone-induced podocyte autophagy[].

... Puerarin. Puerarin, -hydroxy--(-hydroxyphenyl)--benzopyran--one--b-D-glucopyranosid-e, is one o themajor isoavonoid compounds rom the root o Puerariacandollei wall o Leguminosae amily. A previous studyshowed that Puerarin could protect DN rats by inhibitingcollagen IV expression []; urther study in SZ induceddiabetic rats showed that Puerarin could protect kidneyunction through downregulating MMP- and attenuatingeNOS expression [, ].

... Rehmannia Radix (Di Huang). Rehmanniaradix (DiHuang) was mostly mentioned and investigated; it hasbeen proven to reduce hyperglycemia, ameliorate renal dys-unction, prevent senility, and improve hemorheology. Ina previous experimental study Rehmannia radix has beenshown to inhibit the progression o DN []. Catalpol is aniridoid glucoside compound mainly present in Rehmanniaradix and other plants amd has been shown to reduce ECMaccumulation by inhibiting the expression o GF-, CGF,and Ang II in HFD-ed plus SZ induced diabetic rats [].

... Rhein. Rhein (,-dihydroxyanthraquinone--car-boxylic acid) is puried rom rhubarb (Rheum officinale).Rhein has shown reduction o UAE aster than simvastatinand decrease o ECM levels along with decreased GF-and FN immunohistochemistry expression in db/db renaltissue, which was supposed via regulation o dyslipidemia[]. Another study showed that Rhein could inhibit thehypertrophy o rat renal proximal tubular epithelial cellsstimulated by HG and Ang II [].

... Rhodiola rosea. Rhodiola rosea(R. rosea) is grown at

northern latitudes and high altitudes o the world; Rhodiolarosea extract has been used to protect kidney unctionincluding reducing FBG, C, G, Ccr, and h urinaryalbumin in HFD-ed plus SZ induced diabetic rats throughdecreasing renal expression o GF- [].

... Rosa laevigata Michx. (RLM). Rosa laevigataMichx.(RLM), a commonly used CM or the treatment o urinarytract inection and antioxidative treatment, could play acritical role in the pathogenesis o DN through increasingthe activity o SOD and total antioxidant capacity, decreasingMDA and ROS levels, and inhibiting NF-B p and MCP-expression ollowing increased IB protein expression in SZ


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induced diabetic rats; all the data suggested that RLM couldbe a therapeutic potential or DN [].

... Sequoyitol. Sequoyitol is a natural compound presentin a lot o plants (e.g.,Aristolochia arcuata,Amentotaxus yun-nanensis, and Crossostephium chinensis); oral and subcuta-

neous administrations o sequoyitol could ameliorate hyper-glycemia and glucose intolerance in ob/ob mice. Sequoyitolhas been shown to ameliorate the progression o DN in HFD-ed plus SZ induced rats through glucose-lowering effects,antioxidant activity, and regulation o GF- expression[].

... SF/FA. Sodium erulate (SF), extracted rom Angel-ica sinensis, Lignsticum chuangxiong, Cimicifuga heracleifo-lia, and other plants, has platelet aggregation inhibitory,antithrombotic, and antioxidant activities in animals andhumans. A preliminary study on DN patients showed that SFcould lower UAER level and improve renal unction throughdecreasing endothelin (E) and inhibiting the combinationo E with itsreceptor []. A meta-analysis o randomizedcontrolled trials involving patients showed that SF issuperior in reducing UAER, E, BUN, Scr, and C andincreasing HDL-c without affecting FBG and G [].Ferulic acid (FA) is a phenolic acid extracted rom the seedsand leaves o most plants and has antioxidant activities,hypoglycemic and hypolipidemic effects, hypotensive effects,and anti-inammatory effects. In the FA treated OLEF rats,blood glucose and urinary ACR were decreased signicantly;in renal histopathology glomerular basement membranethickness and mesangial matrix expansion were decreasedthrough reducing oxidative stress and inammation [, ].

... Skimmin. Skimmin, a major active component romHydrangea paniculata, has been reported to decrease Scrand blood glucose level and alleviate glomerular segmentalsclerosis and incidence o tubular vacuolar degeneration bydownregulating the GF- and GF- receptor I expres-sion in SZ induced diabetic rats [].

... SM. Salvia miltiorrhiza (SM, commonly known asDanshen in Chinese) has been shown to have the anti-inammatory, antioxidative, and organ protective effects. Aprevious study showed that SM could protect SZ induced

diabetic rats rom DN by suppressing the overexpression oGF-, CGF, PAI-, and FN in renal cortex []. Anotherstudy showed that SM could ameliorate GF- levels inserum and kidney and reduce the levels o collagen IV ED- and RAGE in the diabetic kidney []. Danshen injection,the aqueous extracts o SM, could protect diabetic rats associ-ated with preservation o tubular unction and structure romhyperglycemia induced oxidative stress, advanced glycationstress, and megalin expression deletion [].

... GP. otal glucosides o paeony (GP), extractedrom the root oPaeonia lactiora Pall., have been shownto have the therapeutic effect in the experimental DN. GP

treatment in the SZ induced diabetic rats could prevent dia-betic renal damage against oxidative stress through decreas-ing upregulated p-p MAPK and NF-B P expressions[]. And, in the HFD-ed plus SZ induced rats, GP couldimprove kidney damage and delay the development o DN byinhibiting Wnt/beta-catenin signaling pathway [].

... MP. etramethylpyrazine (MP) is isolated romLigusticum chuanxiongand has been used in the treatmento stroke and cardiovascular diseases. MP was reported toreduce diabetic kidney damage partially by downregulatingthe expression o VEGF in the kidney [].

... riptolide/GW/wHF. riptolide, active diterpenepuried rom ripterygium wilfordii Hook. F. (wHF),has been reported to have anti-inammatory, antioxida-tive, immunosuppressive, and podocyte-protective effects. Arecent study showed that triptolide could attenuate albu-minuria in db/db diabetic mice accompanied with alleviated

glomerular hypertrophy and podocyte injury, while inam-mation and dyslipidemia were also attenuated []. rip-tolideis oneo the major activecomponents o multiglycosideo wHF (GW), and GW has been applied extensivelyor the treatment o CKD in China as an anti-inammatoryagent. GW could prevent glomerular lesion in SZ induceddiabetic model through decreasing urine albumin and ame-liorating glomerular sclerosis []. A recent study showedthat wHF could prevent podocyte injury o DN patients,which may be partly mediated by downregulating the expres-sion o OPN, CGF, and GF- [].

... Volatile Oil of Magnolia biondii Pamp. (VOMBP).Volatile oil oMagnolia biondiiPamp. (VOMBP), extractedrom herbal CMMagnolia biondii Pamp., has been reportedto protect the kidney in SZ induced diabetic rats byinhibiting the expression o P-selectin in serum and renaltissue [].

.. CMs Combined Terapy with Western Medicines inDN. Apart rom the CM preparations and single CMapplications in DN, CMs combined with western medicineshave been indicated. Mostly used western medicines wereACEI/ARBs, and combination styles included angshen-ling (SL) with telmisartan [] in diabetic patients orSL with benazepril in SZ induced rats [], triptolidewith benazepril in DN patients [], Bailing Capsule (BC)

and benazepril in DN patients [], and safflower yellowpowder injection with benazepril in DN patients [].Another report is about angshenqing (SQ) combined withalprostadil in the treatment o DN patients []. All datasuggested that effects o CMs combined therapy with west-ern medicines were superior to western medicines treatmentalone.

3. Conclusions and Perspectives

Although there are almost no side effects mentioned innumerous scientic reports, a lot o scientic researchesindicate that herbal CM preparations have renal protective


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effects on DN according to respective actors, complexity, andvariability o CM preparations still presenting challengesor clinicians seeking scientic evidence to support CMapplication in drug discovery. In order to avoid the toxicityand side effects o CM ormulas, there is increasing interestin studying single herbal CM especially monomers rom

single herbal CM on DN. In this review, we ound thatmonomers such as Berberine, curcumin, Ginsenoside Rg,Puerain, Rhein, and Ferulic acid have specic protectiveeffect on DN. o translate the therapeutic potentials or DNinto reality, placebo-controlled and randomized controlledclinical trials o single herbal CM and/or monomers romherbal CM are essential in the uture, and prompt meta-analysis is an effective alternative.

Conflict of Interests

Te authors have no conict o interests to declare.

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