Research progress of renal interstitial fibrosis

Shi-Jie Liu,XiZhao,Yao-Guang Wang,Man Li

1Tianjin University of Traditional Chinese Medicine,Tianjin,China.2The First Teaching Hospital of Tianjin University of Traditional Chinese Medicine,Tianjin,China.3Tianjin Beichen District Chinese Medicine Hospital,Tianjin,China.

Abstract Renal interstitial fibrosis(RIF)is a common pathological process of chronic kidney disease that progresses to end-stage renal failure.The degree of RIF is closely related to renal function.The study of the pathogenesis of renal interstitial fibrosis,exploration of effective prevention measures to delay the progress of end stage renal disease and prolong the life of patients is significant.The pathology of RIF has complicated extracellular and intercellular mechanisms,involving many cells and cytokines,resulting in an incomplete mechanistic understanding of the disease.Finding effective herbs or herbal extracts for prevention and treatment of RIF is crucial because current medical approaches do not reliably slow or reverse RIF.The research progress of RIF in recent years is summarized as follows.

Keywords:Renal interstitial fibrosis,Research process,Mechanism

Introduction

Renalinterstitialfibrosis(RIF)is a common pathologicalprocessofchronic kidney disease progresses to end-stage renal failure.RIF is a dynamic and slow process,involving a variety of cytokines,inflammatory cell infiltration,renal tubular epithelial-mesenchymaltransition(EMT),renal tubular epithelial cells apoptosis,extracellular matrix(ECM)deposition and degradation imbalances and other factors.The normal renal interstitial and tubular structure is replaced by a large accumulation of extracellular matrix such as collagen,fibronectin and laminin etc.is the pathological features of RIF.

Main factors involved in RIF

The pathophysiology of RIF includes many factors.We concluded as following:

EMT

Under various injury conditions,the EMT is a process by which differentiated epithelialcells undergo a phenotypic conversion and give rise to the activated matrix-producing myofibroblasts.ECM plays an important role in RIF.It is compound and secreted by muscle fiber cells,renal tubular epithelial cells and vascular endothelial cells[1,2].

Plasminogen activator/Plasminogen activator inhibitor(PAs/PAIs)

PAs/PAIs plays an important role in the degradation of ECM.PAs can degrade fibronectin and type IV collagen and other glycoproteins.PAIs is a highly effective physiological inhibitor of PAS,it can inhibit the activation of the fibrinolytic enzyme,so that the MMP precursor into MMP reduced,and it also effectively inhibit the degradation of ECM,resulting in ECM deposition.PAI-1 and PAI-2 are the main form of PAIs,PAI-1 plays an important role in the process of renal interstitial fibrosis.PAs/PAIs can also activate MMPs,form the PAs/plasminogen/MMPs cascade activation effect,and further play a pathological effect.

Matrix metalloproteinase/Matrix metalloproteinase inhibitors(MMPs/TIMPs)

MMPs are mainly secreted by mononuclear cells,macrophages and epithelial cells of renal tubule.Its main function includes degrading most of the ECM protein,activating other MMPs,forming a cascade effect;in the process of cell migration,wound healing,embryonic development and angiogenesis play an irreplaceable role.TIMPs are a specific inhibitor of MMPs,which inhibits the degradation of ECM by inhibiting the activity of MMPs.It has characteristics of growth factor,can regulate cell proliferation and apoptosis.

Myofibroblast is one of the important indicators of poor prognosis of renal diseases

It is the main synthesis cell of growth factor-β1(TGF-β1).The number of it is closely related to the degree of renal interstitial fibrosis.MFB(fibronectin,FN)secrete fibronectin firstly,provide support for the deposition of other ECM components and the formation ofcollagen fibers and then secrete collagen(mainly type I and type III collagen),laminin(LN)and proteoglycans.A large amount of ECM sustained deposition in the renal interstitial,eventually leading to renalinterstitialfibrosis.Myofibroblastplays an importantrole in the synthesis and secretion of extracellular matrix,but its origin is not yet clear.It may come from the following aspects:

Renal fibroblasts:Under normal circumstances,fibroblast is in the resting state,after stimulation can be activated.Activated fibroblastcellsundergo phenotypic and functional changes,which transformed into myofibroblast that express α-smooth muscle actin(α-SMA),and its ability to synthesize ECM was significantly enhanced.Other studies have indicated that the myofibroblast does not need to be activated by fibroblasts,but only root in the proliferation of fibroblasts derived from the stimulation of fibrosis[3].

EMT:EMT refers to the epithelial cells under the influence of some factors,the cell polarity and and the interconnection of cells and the connection between cell and basement membrane lost,differentiate into mesenchymal cells with morphological and phenotypic characteristics,and won themigration ability.Transformed tubular epithelial cells can pass through the rupture of the basement membrane into the renal interstitial,thus directly involved in the process of interstitial fibrosis.Phenotypic transformed renal tubular epithelial cells can secrete fibroblast growth factor 1(FGF-1),plateletderived growth factor(PDGF),TGF-β,intercellular adhesion molecule-1(ICAM-1),osteopontin and a series of cytokines,adhesion molecules and chemokines,and thus it can plays an important role in the process of the regulation of cell chemotaxis and local reaction.But other studies showed that renal tubular epithelial cells did not leave the basement membrane,and did not complete a complete EMT process[4,5].

The most commonly used markers of EMT were E-cadherin,Vimentin,and α-SMA,which confirmed the protein of EMT is β-catenin.When EMT occurs the expression of proteins including α-SMA,FSP1,Vimentin,Fibronectin,Snail1,Snail2,CollagenⅠ,CollagenⅣ,MMP-2,MMP-9increased,the expression of proteins including E-cadherin,ZO-1,Laminin 1 decreased;nuclear accumulation protein including of β-catenin,Smad2/3,Snail,Snail2.

The related regulatory factors that promote the developmentof EMT include TGF-β1[6-9],connective tissue growth factor(CTGF),collagenⅠ.The related regulatory factors thatinhibitthe development of EMT include bone morphogenetic protein(BMP7),which is a member of the TGF-β superfamily of endocrine type multifunctional protein,in addition to the inhibition of TGF-beta 1 induced the occurrence of EMT,but also can effectively inhibit MCP-1 induced EMT process.

Intracellular signal transduction pathway of EMT in RIF is TGF-β1 signal transduction pathway,activated TGF-β1 and I,II receptor binding through Smad or non-dependent Smad signaling pathway regulates EMT process.TGF-β1 also activates ERK MAPK,p38-MAPK and JUN N-terminal domain active(JUK)pathway[10].

Pericytes:pericytes exist in the capillaries and distribution in endothelial cells,contact with endothelialcells,underthe pathologicalinjury pericytes migrate,proliferate,differentiate into myofibroblasts[11-19].The mechanism may be related to the activation of VEGF signaling pathway,the promotion of endothelial cell proliferation,and then the release of PDGF and TGF-β that promote the proliferation and differentiation of pericytes[20][21].Other studies have found that macrophages can also promote the proliferation and differentiation of pericytes[22].

Endothelial mesenchymal cell transformation(EndMT):the study confirmed that the contribution of EndMT to myofibroblasts was only 10%[3].

Bone marrow derived muscle fibroblasts:the study confirmed that bone marrow cells are also one of the sources of the myofibroblasts.The role of myofibroblast in the process of renal interstitial fibrosis:A large number of growth factors and cytokines interact promote the proliferation and activation of myofibroblasts in the occurrence of renal injury.The rapid increase of myofibroblast lead to the increase of ECM,mainly including collagen I,III,IV,glycoprotein and protein,and so on.At the same time,it can also secrete TIMPs,such as PAI-1,so that the degradation activity of MMP decreased,and thedegradation ofECM decreased.This combination lead to the synthesis of ECM increase and thedecomposition ofECM reduced,and promote the ECM deposit in the kidney continuously.

The role of inflammatory cell infiltration in the process of renal interstitial fibrosis

A large number of inflammatory cell such as macrophages,lymphocytes,monocytes etc.infiltrated in the renal interstitial and damaged parts.Macrophages can secrete proinflammatory cytokines and fibrogenic factor such as TGF-β and fibroblast growth factor(FGF)and insulin-like growth factor(IGF),interleukin-1 and epidermal growth factor,resulting ECM deposit in renal interstitial.

The role of TGF-β in the process of renal interstitial fibrosis

TGF-β is mainly expressed in the glomerular and tubular cells,and the expression is very weak in normal kidney.TGF-β1 is recognized as the most important cause of fibrosis,and its expression is closely related to RIF.The function of TGF-β is:stimulate fibroblastproliferation and activation;inhibitthe activity ofmatrix metalloproteinase(MMPs)and plasminogen activator(PA),increase the synthesis of tissue inhibitors of metalloproteinase(TIMPs)and plasminogen activatorinhibitor1(PAI-1),consequently inhibit the degradation of ECM;stimulate renal tubular epithelial cells trans-differentiation into myofibroblasts[23-25],TGF-β1caninduceEMTviaSmads,MAPK,Akt/protein kinase B and WNT/βcatenin signaling pathways,eventually lead to RIF[26,27];promoting renal tubular interstitial cells synthesis collagen;inducing the expression of connective tissue growth factor(CTGF)and cytokine secretion,promoting the produce of ECM;regulating autophagy[28].

The role of CTGF in the process of renal interstitial fibrosis

Under the action of a variety of factors,a lot of renal cells can produce CTGF,tumor necrosis factor-α(TNF-α),and bone morphogenetic protein-7(BMP-7).The expression of nitric oxide can inhibit the CTGF.The direct effect of CTGF on renal mesangial cells including migration,hypertrophy,the synthesis of fibronectin,the decomposition of actin,EMT in tubularepithelialcellsand interstitial fibroblasts produce collagen and TSP-1.CTGF is a downstream effector of TGF-β.Studies have confirmed that CTGF and TGF-β1 can reduce the MMP-2 produced by fibroblasts and promoted their conversion to myofibroblast,which resulted in the promotion offibrosis.CTGF can mediatethe production of collagen of human mesangial cells,resulting in the deposition of ECM and EMT.CTGF can also induce inflammation and participate in the enablement of RIF.

TheroleofMonocytechemoattractant protein-1(MCP-1)in the process of renal interstitial fibrosis

The normal kidney tissues secrete trace MCP-1,and when the renal tissue is stimulated,the expression of mRNA and protein of MCP-1 increased significantly,and the degree of renal damage was positively correlated.Studies have shown that MCP-1 may increase the expression of collagen mRNA through theTGF-β,which promotesthedeposition of extracellular matrix proteins,which ultimately leads to RIF[29].

The role of reactive oxygen species(ROS)in the process of renal interstitial fibrosis

ROS can promoteinflammatory cellsin renal aggregate,mediate chemokine(MCP-1)and a large number of adhesion molecules release,promote the occurrence of renal fibrosis[30,31].ROS can induce the production of Ang II,TGF-β,epidermal growth factor and other key cytokines,and further induce the RIF[32].Active oxygen can stimulates TGF-β1 release in active form by c-Jun amino terminal kinase/mitogen activated protein kinase pathway,the release of a large number of TGF-β1 can induce the deposition of collagen and fibronectin,then the regulation of ECM.Active oxygen and TGF-β1 can reduce the expression of E-cadherin and increase the expression of α-SMA to upregulated the expression of plasminogen activator inhibitor and fibronectin to induce EMT in renal tubular epithelial cells[33].Activated oxygen can promote the expression of α-SMA by activating NF-κB to promote EMT.

The role of oxidative stress in the process of renal interstitial fibrosis

When the oxidative stress activated in the renal,the production of ROS increased,the expression of p-p38MAPK increased,so as to activate the p38MAPK signaling pathway.Thep38MAPK signaling pathway promote the downstream products ofTGF-β1generation by regulating the gene transcription and protein expression,leading to mesangial cell proliferation and deposition of ECM,and ultimately exacerbate the process of RIF[34].ROS can induce the expression of TGF-β1,leading to glomerular basementmembrane expansion,stimulate fibronectin and collagen expression,play an important role in RIF and EMT[35].Studies show that by inhibiting the MDA,improve the vitality of SOD,can reduce the expression of P38MAPK protein,thereby reducing the rat's kidney damage and inhibit renal interstitial fibrosis[36].ROS can activate P38MAPK;it can inhibit the activation of P38MAPK by inhibiting the production of ROS[37].

The role of hepatocyte growth factor(HGF)in the process of renal interstitial fibrosis

The experimental results show that in the case of persistent renal injury,the endogenous HGF sustained high expression can effectively inhibit the process of RIF.The mechanism could be as follows:activate the degradation pathway of ECM.The degradation of ECM is mainly mediated by MMPs system,HGF can promote the expression of MMP-9,inhibit the expression of TIMP,and thus reduce the deposition of ECM,inhibit EMT.The experiment found that HGF can prevent EMT caused by TGF-β1,block the transduction of TGF-β1/Smad signal,reduce the growth of CTGF mediated by TGF-β;inhibit cell apoptosis.In pathological conditions,HGF can contribute to the integrity of the function of the kidney.

The role of augmenter of liver regeneration(ALR)in the process of renal interstitial fibrosis

The study confirmed that ALR can not only inhibit cell apoptosis in the early stage of injury of renal tubular epithelialcells,butalso promote the proliferation of injured renal tubular epithelial cell.Studies have confirmed that ALR can inhibit the phosphorylation of Smad2 and Smad3 proteins,thereby inhibiting the TGF-β/Smad signaling pathway and inhibiting renal interstitial fibrosis[38].Studies have confirmed that ALR can enhance the activity and expression of MMP-9 by reducing the expression of TIMP-1,thus promoting the degradation of ECM.ALR could significantly inhibit the activation of the phosphorylation of P38MAPK cells,thereby blocking the activation of P38MAPK signaling pathway,inhibit renal inflammation reaction,thereby reducing the damage of renal tissue and delay the process of renal interstitial fibrosis.

The role of mast cells(MCs)in the process of renal interstitial fibrosis

The study suggests that there is a relationship between MCs infiltration and interstitial fibrosis,MCs may be involved in the accumulation of ECM in interstitial nephritis.Other studies suggest that MCs inhibits the progression of fibrosis,the accumulation of collagen I,protects the E-calcium mucin,inhibitstheexpression ofα-SMA,and reduces the expression level of TGF-β1 in tissues.

The role of BMP-7 in the process of renal interstitial fibrosis

BMP-7can affect the signalof TGF-β1/Smad pathway to decrease the expression of pro-inflammatory cytokines,activate the degradation of ECM,inhibit the apoptosis of epithelial cells and maintain the phenotype of epithelial cells.BMP-7 can also produce anti fibrosis effect by inducing the expression of MMP-2.

The role of Smad7 in the process of renal interstitial fibrosis

Studies show that the levels of Smad7 can modulate the intensity and duration of TGF-β,and that the deficiency of Smad7 can lead to renal interstitial fibrosis.

The role of miRNA in the process of renal interstitial fibrosis

Recently studies have indicated that miRNA has a clearly expression in the progression ofrenal interstitial fibrosis.

MiRNA-200:Studies show that the miRNA-200 family has a role in maintaining epithelial phenotype and participates in the regulation of EMT.The miRNA-200 family,especially miRNA-200b can inhibit the transcription factor to inhibit ZEB1 and ZEB2 E-cadherin by homologous target,so as to increase the level of E-cadherin,inhibit renal tubular epithelial cells to mesenchymal transition,delay the progress of RIF[39-41].Studies have indicated that miRNA-200a overexpression inhibits the expression of TGF-β2,reduces the activity of Smad3 and alleviates the extracellular matrix synthesis induced by TGF-β1,thus inhibiting renal fibrosis.

MiRNA-21:A large number of studies have indicated thattheexpression ofmiRNA-21is significantly up-regulated in the animal model of renal fibrosis and the renal tissue of the patients,and the expression level of miRNA-21 is closely related to the renal interstitial fibrosis[42].Research shows that the expression of miRNA-21 was significantly increased in diabetic mice,the expression of miRNA-21 and TIMP1,collagen IV and fibronectin is positive correlation,suggesting renal fibrosis is closely related to miRNA-21[43,44].The experiments showed that the deficient of miRNA-21 gene mice reduced renal tubular atrophy and renal fibrosis[45].

MiRNA-21 can promote TGF-β and promote fibrosis by inhibiting Smad7.TGF-β can activate the ERK/MAP kinase signal and inhibit apoptosis and promote fibroblast proliferation[46].

MiRNA-29:A number of studies have indicated that the miRNA-29 family is involved in renal fibrosis[47].The miRNA-29 family directly acts on a large number of extracellular matrix genes and reduces renal interstitial fibrosis.MiRNA-29 is a downstream inhibitor of TGF-β/Smad3 mediated fibrosis[48],TGF-β1 will reduce the expression of the miRNA-29 family,in order to increase the expression of collagen gene and extracellular matrix,and promote renal fibrosis.

MiRNA-34a:The study showed that EMT induced by hypoxia can decrease the targeting expression in Notch1 and Jagged1 miRNA-34a,and then start the Notch signaling pathway to promote the process of EMT[49].

MiRNA-216a:The expression of miRNA-216a im mesangialcells can be up regulated by the stimulation of TGF-β,resulting in increased expression of collagen IA2,and promote the process of fibrosis[50].

MiRNA-302:Studies have found thatthe miRNA-302 family can attenuate the proliferation,fibrosis,and thrombosis induced by TGF-βand EMT induced by TGF-β[51].

MiRNA-192:Studies have found that TGF-β is ableto up regulatethelevelofmiRNA-192,miRNA-192 can regulate the production of collagen by acting on the expression of SIP1 and ZEB1mRNA,participate in the promotion of extracellular matrix accumulation induced by TGF-β.The experiment confirmed that the inhibition of miRNA-192 could decrease the expression of collagen and fibronectin,thereby inhibiting renal fibrosis[52].

MiRNA-433:Recently studies have found that miRNA-433 plays an important role in renal fibrosis through the TGF-β/Smad3pathway.TGF-β stimulates the expression of miRNA-433 in renal tubular epithelial cells,which promotes fibrosis,miRNA-433overexpression promotes the accumulation of collagen matrix in renal tubular epithelial cells induced by TGF-β1[53].

The role of peritubular capillaries in the process of renal interstitial fibrosis:present study shows that the reduction of peritubular capillaries may play an important role in renal tubular damage and interstitial fibrosis[54-56].When kidney injured,endothelial cell corresponding signaling pathway start,stimulate near cells,resulting in the normalrelationship between endothelial cells and pericytes destroyed,the stability of peritubular destruct and ischemic renal injury,leading to renal interstitial fibrosis[57,58].Some studieshave indicated thatVEGF,angiogenin-1,angiogenin-2,NO,NOS and hypoxia inducible factors are involved in the changes of the capillary of renal tubule.

The role of nitric oxide(NO)in the process of renal interstitial fibrosis

NO is a relaxing vascular substance that synthesized and released by PTC.Previous studies showed that it can aggravate the degree of renal fibrosis in UUO model rats by gene knockout or specific inhibition of iNOS,and the less the content of NO,the more serious the degree of fibrosis.NO can also down-regulated to regulate EMT induced by TGF-β1,it plays an important role in RIF.

The role of endothelin(ET)in the process of renal interstitial fibrosis

ET is a powerful and profibrosis factor,which is involved in the occurrence and development of RIF.The mechanism may be follows:ET promotes the production TGF-β1,TIMP-1,involved in the process of RIF;through its potent vasoconstriction effect,significantly reduced the blood flow of renal,reduce glomerular filtration rate,increase the injury of renal tissue;promote the contraction of glomerular mesangial cell,then glomerular filtration rate and filtration area is further reduced,trigger inflammatory reactions.The release of inflammatory cytokines,mediate the deposition of ECM,accelerate the process of RIF;cultured renal tubular epithelial cells that cultured in high glucose environment,it is found that the ET-1 content increased significantly,accompanied with EMT,ECM degradation and induced imbalance,the production of RIF[59].

The role of angiotensin II(Ang-II)in the process of renal interstitial fibrosis

The renin angiotensin system(RAS)is activated in the pathogenesis of chronic renal interstitial fibrosis.Ang-II is the main bioactive peptides in RAS to promote the kidney damage,it can activate the renal epithelial cells,stromal fibroblasts and glomerular cells,adjust the cell growth and ECM synthesis.Ths mechanism that Ang-II may promote RIF is:Ang-II directly activates Smad signaling system and EMT induced by TGF-β/Smad;promote the synthesis and secretion of CTGF and TGF-β1 and some other cytokines;activate of JAK/STAT signaling pathway,leading to the increase of extracellular matrix such as FN.

The role of peripheral blood cells in the process of renal interstitial fibrosis

The angiogenic factors secreted by peripheral support the integrity of the vessel.The destruction of its structure and function can affect the stability of the blood vessel,and the decrease of the capillary of renal tubule has a relationship with renal interstitial fibrosis[56,60].

The role of heme-1(HO-1)in the process of renal interstitial fibrosis

Studies have demonstrated that the deficiency of HO-1 in the UUO rat model may contribute to the renal tubular epithelial differentiation and promote theoccurrence ofRIF.Studiesshow thatthe expression of HO-1 can slow down or even reverse the progression ofrenalinterstitialfibrosisby decreasing EMT[61-63].

The role of signaling pathways in the process of renal interstitial fibrosis

The role of P38MAPK signaling pathway in the process of renal interstitial fibrosis:

P38MAPK signaling pathway is the classical pathway of renal interstitial fibrosis.P38MAPK signal pathway play an important role in the process ofrenalfibrosis,the inhibition ofP38MAPK signaling can delay the progression of RIF,high expression of p-P38MAPK/P38MAPK can activate the renal tubular epithelial cells,resulting in the production of α-SMA,induce the process of RIF.P38MAPK can promote the production of glomerular mesangial cells and fibroblast like protein and collagen matrix induced by TGF-β.There was a significantinteraction between P38MAPK and TGF-β1.On one hand,TGF-β1 gives play to its biological activity by stimulating the activity of P38MAPK,on the other hand,as the downstream productofP38MAPK signaling pathway,the increased synthesis of TGF-β1 can aggravate renal interstitial fibrosis.

The role of Notch signaling pathway in the process of renal interstitial fibrosis

The Notch pathway is the"non-Smad"channel for delayed activation of TGF-TGF-β1[64].Studies confirm that the Notch pathway is essential for the generation of α-SMA and ECM mediated by TGF-β[65].Notch can accelerate the phosphorylation of TGF-β1/Smad3 protein,and increase the content of α-SMA,strength the accumulation of actin and improve the microtubule cytoskeleton system,thereby causing the damage of small basement membrane,eventually making myofibroblast infiltration and transferring to interstitial,the excessive deposition of matrix[66].The experiment confirmed that the Notch pathway promote the process of RIF mediated by TGF-β by regulating the downstream regulatory target gene Snail[67,68].It was found the expression of Notch1/Jag1 increased in patients with renal injury and renal tubules interstitial fibrosis[69].A number of experiments found the renal tubular interstitial fibrosis was significantly reduced by using specific Notch signal blocking agent,the Notch signal participate in the process of renal tubular interstitial fibrosis[66,70].The study found that activation of the Notch pathway can improve the expression of inflammatory factors such asinterleukin-6,MCP-1, α-SMA,NF-κB,reduce the content of E-cadherin protein in cells[71].In addition to TGF-βsignaling,Notch pathway may also play a regulatory role in Shh,Wnt/β-catenin,Ras,EGFR,VEGF,and othersignaling pathways associated with renal fibrosis[66].

The role of JAK/STAT signaling pathway in the process of renal interstitial fibrosis

A study has found that the JAK/STAT signaling pathway plays an important role in the renal injury induced by Ang-II[72].JAK/STAT pathway can mediate the pathological activation and damage of macrophages,fibroblasts and renal tubular epithelial cells in the process of renal interstitial fibrosis,and it has an important regulation effect on renal interstitial fibrosis.

The role of SHh pathway in the process of renal interstitial fibrosis

Recently studies have found that SHh signaling pathway plays an important role in various organs fine process,SHh signaling pathway may upregulate the expression of Snail,EMT.Studies show that the activation of SHh signaling pathway can induces the expression and release of TGF-β,leading to renal interstitial fibrosis.

The role ofVEGF/VEGFR signaling pathway in the process of renal interstitial fibrosis

The VEGF/VEGFR signaling pathway is important in maintaining the stability of peripheral blood capillaries and in the differentiation of peripheral.Activation of VEGF can lead to the transfer of peripheral and infiltration of macrophages,long-term VEGF can lead to microvascular injury,fibrosis.The experimental results confirmed that the blocking of VEGF has a significant effect on interstitial fibrosis[15,26].

The role of PI-3K signaling pathway in the process of renal interstitial fibrosis

Inhibit the activation of PI-3K may attenuate the phosphorylation and subsequenttranscription of Smad in the TGF-beta 1 pathway,and attenuate the occurrence of EMT in the tubular epithelial cells.

Renal interstitial fibrosis is the excessive deposition of extracellular matrix caused by a variety of reasons resulting in renal interstitial inflammation and fiber formation,the degree of renal interstitial fibrosis is closely related to renal function.As the most important factors that influence the change of renal function,researchers paid much more attention to renal interstitial fibrosis.Do further research of pathogenesis of renal fibrosis,explore effective prevention measures to delay the progress of end stage renal disease,prolong the life of patients has important significance.Although with the deepening of the research,the pathogenesis of renal interstitial fibrosis is gradually being known,but there are still a lot of unclear and controversial,still need to be further studied.

Modern medicine treatment for RIF

Development of RIF is a complex process that involves multiple factors and system interaction.Currently available treatments cannot effectively slow the progression of RIF and improve renal graft function.Some newly developed approaches may be beneficial for prolonging renal graft survival in the future.Those strategies include anti-EMT agents,antioxidant therapy,tubular epithelial cell repair,and mesenchymal stem cell therapy.Oxidative stress inhibition is likely to be involved in delaying the progression of renal interstitial fibrosis.Evidence indicates that alpha-lipoic acid(ALA)is a powerful antioxidant and exhibits a protective effect against renal injury.ALA also improves albuminuria and pathology in diabetes by reducing oxidative stress.However,special Western drugs against RIF are still being investigated in experiments or clinical trials.

Traditional chinese medicine herbs with anti-RIF function

In recent years,traditional chinese medicine has certain curative effects on the treatment of renal interstitial fibrosis,experimental study that traditional chinese medicine can prevent and treat renal interstitial fibrosis have been done,many chinese herbs and its extract,compound has the function of anti-renal fibrosis.The related mechanism of traditional chinese medicine in the treatment of renal interstitial fibrosis is briefly introduced as follows:

Chinese herbs and extracts

Salvianolic-acid B can delay renal fibrosis,its mechanism is it can inhibit the expression of α-SMA,maintain the phenotype of epithelial cells,thereby delaying the occurrence of renal fibrosis[73].

PNS can reduce the expression of TGF-β1 and Smad2 of rats with unilateral ureteral obstruction(UUO)and upregulate the expression of BMP-7 and Smad 7.It is indicated that the anti-fibrosis function of PNS may be through the intervention of the BMP-7/Smads/TGF-β1 signal transduction pathway,which inhibits the intracellular transduction of the TGF-β1 signal[74].Another study shows that ginseng totalsaponin(Rg1),the main activity monomer of sanqi total saponin,can inhibit the expression of TGF-β1 and α-SMA in renal tissue to reduce renal interstitial fibrosis[75].

With the treatment of Safflower,the expression of nuclear factor κB and TGF-β1 decreased,showed Safflower can inhibit renal interstitial fibrosis by inhibiting κB and TGF-β1[76].

Zedoary can make renal fibrosis model of UUO rats’TGF-β1 and connective tissue growth factor(CTGF)expression decreased obviously,zedoary is probably by reducing the expression of TGF-β1 to inhibit the secretion of CTGF,thus alleviate the fibrosis caused by renal injury[77].

The mechanism of Ligustrazine can delay RIF is it can reduce the expression of MMP-9 and TIMP-1[78].

Salvia miltiorrhiza injection can reduce the lesion of epithelial cells,inflammatory cells infiltration and interstitial hyperplasia,thus reducing renal interstitial fibrosis[79].

Emodin can reduce the content of serum collagen typeⅠ(C-Ⅰ)and procollagenⅢ(PⅢP)and hyaluronic acid(HA),reduce the expression of TGF-β mRNA in renal tissue.It is suggested that emodin may play a role in anti-fibrosis by inhibiting the expression of TGF-β in rat’s kidney[80].

Alisma Orientalis can reduce the expression of C3 and α-SMA,increase the expression of E-cadherin(E-cadherin),inhibit EMT,alleviate renal interstitial fibrosis[81].

Tufuling can significantly improve the levels of NO and NO/ET values of DN rats decrease the renal index inhibitthe expression ofTGF-β1.The therapeutic mechanism of Tufuling may be inhibit the expression of TGF-β1 and relax diastolic blood vessels in the kidney[82].

Astragalus can significantly alleviate renal fibrosis,decrease the expression of TIMP-1 in renal,increase the expression of MMP-9.It showed that Astragalus could regulate the MMP-9/TIMP-1 balance to give play to itsanti-fibrosiseffect[83].Astragalus Injection probably alleviates RIF by inhibiting the expression of TGF-β,inhibit the transdifferentiation of renal tubular epithelial cells[84].

Eucommia can inhibitthe overexpression of GTGF and enhance the expression of MMP-2,thereby slowing the progression of renal fibrosis[85].

Ginseng monomer can inhibit the proliferation of activated renal fibroblasts,effectively prevent and trea renal fibrosis.Its possible mechanism is related to the inhibition of the secretion of TGF-β1[86].

Chinese medicine compound

Jianpi Qinghua Decoctioncan reduce renal inflammation by downregulating the expression of TNF-α in rats with renal fibrosis,thereby playing the role of anti-renal fibrosis[87].

Zishen Huoxue recipe can reduce the content of HA,LN in rats with renal fibrosis,inhibit the expression of TGF-β1 in renal tissue,and delay the development of renal fibrosis[88].

Yishen Huayu Formula may inhibit the high expression of TGF-β1in ratmodelofUUO,upregulate the expression of Smad7,thus alleviate renal interstitial fibrosis[89].Yishen Decoction can reduce the expression of TGF-β1 and ET-1 in renal tissue of DN[90].

Shefuning granular preparation can inhibit the expression of α-SMA in renal tissue of rats with renal fibrosis,alleviate renal fibrosis[91].

Paidu Baoshen Pill can delay the progress of renal fibrosis by downregulating the expression of TGF-β1 and FN[92].

Zhen Wu Decoction can decrease the content of FN,collagenⅢ, α-SMA and Cys-C in serum,delay the progress of renal fibrosis of UUO rats[93].

Quyu Huatan Decoction can delay the progress of renalinterstitialfibrosisby downregulating the expression of TGF-β1,inhibiting the occurrence of EMT of UUO rats[94].

Buyang Huanwu Decoction can inhibitthe expression of TGF-β1,Smad2, α-SMAmRNA and P-Smad2 protein,activate Smad7mRNA,suggesting thatBuyang Huanwu Decoction may play a protective effecton the kidney by regulating TGF-β1/Smads pathway,inhibiting myofibroblast transform into abnormal cells[95].Buyang Huanwu Decoction can improve renal function and renal tubulointerstitial fibrosis by reducing the expression of collagen fiber and TGF-β1[96].

Astragalus and Notoginseng can reduce the deposition of collagen in renal interstitial and renal pathological damage,reduce the content of OH and MDA,increase the content of SOD.It showed that it could improve the RIF of rats with UUO induced by oxidative stress[97].

Huangqishanjifang can downregulate the expression of TGF-β1,FN,so as to improve the renal interstitial injury and renal interstitial fibrosis[98].

Paidu Baoshen Pill can reduce the content of TGF-β1,PC III,Col IV,LN,FN in blood,reduce the expression of TGF-β1 and FN in renal tissue.The function of anti-renal fibrosis was induced by gene transcription and protein translation,which reduced the expression of TGF-β1 and FN[99].

Jianpiyishen Decoction can effectively reduce the expression ofTGF-β1in renaltissue,thereby slowing the development of renal fibrosis,delaying the progress of CRF[100].

Jiedu Fushen Zhuyu fang can significantly reduce the area of the deposition of collagen,inhibit the expression of TGF-β1and CTGF proteins,suggesting that Jiedu Fushen Zhuyu fang could inhibitthe production ofTGF-β1,reduce the synthesis of CTGF,inhibit the deposition of ECM,so as to achieve the function of prevent and treat of renal fibrosis[101].

Yishen Huayu Recipe can decrease the expression of α-SMA,increase the expression of E-cadherin.It is indicated that Yishen Huayu Recipe may inhibit the high expression of α-SMA,upregulate the expression of E-cadherin,thus playing the role of anti-renal interstitial fibrosis[102].

Shen Xian Kang can inhibit the RIF of UUO rats by downregulating the expression of TGF-β1,Smad2,Smad3in renalinterstitialand increasing the expression of Smad7.It can also alleviate the micro inflammatory state by reducing the expression of TNF-α and IL-6[103].

Xiao-zheng San-jie Method can alleviate renal interstitial fibrosis of UUO rats by inhibiting the expression of CTGF[104].

Hejie Jusan Formula can downregulate FN and ColIV in differenttimes,thus improving renal interstitial fibrosis in rats[105].

Huoxue Quyu Decoction can downregulate the level of NAG and β2-MG in UUO rats.It is indicate that it can delay the progress of renal fibrosis by inhibiting the overexpression of TGF-β1 and CTGF[106].

Paidu Baoshen decoction can inhibit renal fibrosis by inhibiting EMT[107].

Shenshuai xiezhuo Pill can delay the progress of renal interstitial fibrosis and its mechanism is it can inhibit the transduction of TGF-β1 signaling to the nucleus by reducing the expression of Smad2/3 and TGF-β1[108].

Huayu Xiezhuo Recipe can improve the pathological damage in renal tissue of UUO rat,inhibit renal fibrosis[109].

Qudu Granules can improve renalinterstitial fibrosis.The mechanism may be related to it can downregulate the expression CTGF and Col I,upregulate the expression of HGF and BMP-7 in renal tissue[110].

Fangji huangqi Decoction can reduce the level of renal monocyte chemoattractant protein-1m RNA transcription,inhibiti EMT,improve renal interstitial fibrosis[111].

Simiao Powder can improve the morphology of HK-2 cells induced by uric acid,downregulate the expression of TGF-β1,α-SMAmRNA,upregulate the expression ofE-Cadherin mRNA,inhibitthe occurrence and development of EMT[112].

Zhenwu Decoction can inhibit the expression of Ang-II and IL-K in blood and FN and MMP-9 in tissue[113].

JianpiQinghua Decoction can increase the activity of SOD,decrease the content of MDA,downregulate the expression of AT1 protein and p47phoxmRNA in renal tissue.It is indicate that it can reduce the expression of ATII and NADPH oxidase,thereby improving oxidative stress in rats with chronic renal failure,delay the progress of renal fibrosis[114].

Spleen and Kidney Reinforcing Therapy can downregulate the expression of TGF-β1 and CTGF,inhibit the synthesis of ECM,alleviate RIF,and ultimately delay the progress of chronic renal failure[115].

Conclusion

To date,some cellular and molecular mechanisms of RIF have been highlighted in research worldwide;however,special Western drugs against RIF are still being investigated in experiments or clinical trials.There are thousands of herbs used medicinally in China,and hundreds of herbs that are frequently used to treat kidney diseases.It is likely that highly effective active ingredients from known herbs are awaiting discovery and exploration.