Hepatocyte growth factor: Renotropic role and potential therapeutics for renal diseases

Kidney International, Vol. 59 (2001), pp. 2023–2038

PERSPECTIVES IN BASIC SCIENCE

Hepatocyte growth factor: Renotropic role and potentialtherapeutics for renal diseases

KUNIO MATSUMOTO and TOSHIKAZU NAKAMURA

Division of Biochemistry, Biomedical Research Center, Osaka University Graduate School of Medicine, Osaka, Japan

Hepatocyte growth factor: Renotropic role and potential thera- unrecognized. Understanding the molecular mechanismspeutics for renal diseases. Hepatocyte growth factor (HGF), a involved in regeneration systems will lead to new clinicalligand for the c-Met receptor tyrosine kinase, has mitogenic, strategies to combat renal disease, as is now the case formotogenic, anti-apoptotic, and morphogenic (for example, in-

the immune and neuroendocrine systems.duction of branching tubulogenesis) activities for renal tubularPatterns of tissue regeneration are mainly divided intocells, while it has angiogenic and angioprotective actions for

two distinct systems. One is the “stem cell system.” Inendothelial cells. Stromal cells such as mesangial cells, endothe-lial cells, and macrophages are sources of renal HGF; thus, tissues, such as nervous and muscle, stem cells usuallyHGF mediates epithelial–stromal and endothelial–mesangial remain in a quiescent and undifferentiated state (butinteractions in the kidney. In response to acute renal injury, committed to differentiate into specific cell types), yetthe expression of HGF increases in the injured kidney and in

they proliferate to produce daughter cells that will differ-distant intact organs such as the lung and spleen. Locally andentiate into the required tissues, in response to injuries.systemically increased HGF supports renal regeneration, possi-The other is a “simple duplication system.” In parenchy-bly not only by enhancing cell growth but also by promoting

morphogenesis of renal tissue. During progression of chronic mal organs such as the kidney and liver, differentiatedrenal failure/renal fibrosis, the expression of HGF decreases cells proliferate without dedifferentiation to replace ex-in a manner reciprocal to the increase in expression of trans- cised or injured tissues. Thus, to understand mechanismsforming growth factor-b (TGF-b), a key player in tissue fibrosis.

involved in renal and hepatic regeneration, the followingA decrease in endogenous HGF, as well as increase in TGF-b,issues must be addressed: (1) how differentiated cellsaugments susceptibility to the onset of chronic renal failure/recognize injury or partial removal of tissues even thoughrenal fibrosis. On the other hand, supplements of exogenous

HGF have preventive and therapeutic effects in cases of acute the remaining cells are apparently intact; (2) which tropicand chronic renal failure/renal fibrosis in laboratory animals. factors are responsible for regeneration; and (3) howHGF prevents epithelial cell death and enhances regeneration differentiated cells proliferate and reorganize tissue-spe-and remodeling of renal tissue with injury or fibrosis. A reno-

cific multicellular architectures.tropic system underlies the vital potential of the kidney toBoth the kidney and the liver have a vital capacity toregenerate, while an impaired renotropic system may confer

regenerate. After unilateral nephrectomy, a compensa-susceptibility to the onset of renal diseases. Thus, HGF supple-mentation may be one therapeutic strategy to treat subjects tory renal enlargement occurs and blood-borne “reno-with renal diseases, as it enhances the intrinsic ability of the tropin” is present that enhances renal regeneration [1, 2].kidney to regenerate. Although renotropin(s) has yet to be clearly identified,

the renotropic system is considered to support the intrin-sic ability of the kidney to regenerate in response to

Animals, including mammals, share the intrinsic abil- injury. Studies done in the 1990s have shown that hepato-ity to regenerate specific tissues and organs. This unique cyte growth factor (HGF) qualifies as a candidate forpotential to regenerate damaged or lost tissues is a bio- renotropin. An increase and a decrease in expression oflogical defense system, and many therapies depend on renotropic HGF are respectively involved in renal regen-the intrinsic regeneration potential (for example, treat- eration and susceptibility to the onset of diseases suchment for bone fracture), although this notion often goes as fibrosis of the kidney. This review focuses on the

renotropic functions of HGF for renal regeneration/pro-tection and the potential of HGF to treat humans with

Key words: acute renal failure, cell regeneration, chronic renal failure, renal disorders.renal fibrosis, morphogenesis.

Received for publication August 31, 2000 BACKGROUNDand in revised form November 14, 2000Accepted for publication November 16, 2000 Hepatocyte growth factor, first identified [3, 4], puri-

fied [5–8], and cloned [9, 10] as a potent mitogen for fully 2001 by the International Society of Nephrology

2023

Matsumoto and Nakamura: HGF in renotropic systems2024

Fig. 1. Schematic structures. (A) Prohepato-cyte growth factor (HGF) and mature HGF.(B) Typical biological activities of HGF medi-ated by c-Met/HGF receptor and intracellularsignal transducers which associate with tyro-sine-phosphorylated c-Met.

differentiated hepatocytes, is a heterodimeric molecule single-chain precursor form, and processing by specificserine proteases into the two-chain form is coupled tocomposed of a 69 kD a-chain and a 34 kD b-chain [6–8].

The a-chain contains the N-terminal hairpin domain and its activation (Fig. 1A). HGF activator, a serine proteaseresponsible for activation of HGF, has structural similar-the subsequent four kringle domains, and the b-chain

contains a serine protease-like domain (Fig. 1A) [9, 10]. ity to blood coagulation factor XII [11]. Involvementof urokinase-type plasminogen activator (uPA) in theThe kringle domain was initially found in serine proteases

involved in blood coagulation or thrombolysis, and HGF activation of pro-HGF was also reported [12].Hepatocyte growth factor has multiple biological activi-has a 38% amino acid sequence homology to plasminogen.

Plasminogen is composed of a five kringle-containing ties on a wide variety of cells, including mitogenic, moto-genic (enhancement of cell movement), morphogenic, andA-chain and B-chain of the serine protease catalytic sub-

unit, whereas HGF has no serine protease activity because anti-apoptotic activities (Fig. 1B) [13–19]. The motogenicaction of HGF was deduced from the unexpected findingamino acids are substituted in the catalytic center. HGF

is biosynthesized and secreted in a biologically inactive that characterization of scatter factor showed it to be

Matsumoto and Nakamura: HGF in renotropic systems 2025

identical to HGF [20–22]. Scatter factor was originally creasing cadherin-mediated cell–cell adhesion, respec-tively. In addition to transphosphorylation-dependentidentified and purified as a fibroblast-derived epithelial

cell motility factor [23–25]. HGF affects cell–cell interac- signaling pathways, the induction of gene expression ofproteins involved in cell-associated proteolytic break-tion and cell–extracellular matrix (ECM) interaction and

stimulates or activates proteolytic networks involved in down of ECM components plays an important role inbranching tubulogenesis, including uPA, uPA receptor,the breakdown of ECM proteins [26–29]. Thus, typical

biological activities of HGF are involved in construction, and membrane-type 1 matrix metalloprotease (MT1-MMP) [26–28]. In terms of anti-apoptosis, the activationremodeling, and protection of tissue structures during

development and regeneration. of PI-3 kinase and downstream Akt (protein kinase B)[47] and the induction of Bcl-2/Bcl-xL are likely path-The receptor for HGF was identified in 1991 to be a

c-met protooncogene product [30, 31]. The c-Met receptor ways responsible for protection of cells from apoptosisby HGF [48, 49].is composed of a 50 kD a-chain and a 145 kD b-chain

[32]. The a-chain is exposed extracellularly, while the The essential role of HGF and the c-Met receptor inmammalian development was defined by disruption ofb-chain is a transmembrane subunit containing an intra-

cellular tyrosine kinase domain (Fig. 1B). Binding of HGF or the c-Met gene in mice; these animals died onembryonic days 13 to 15 because of impaired organogene-HGF to the Met receptor induces activation of tyrosine

kinase, which results in the subsequent phosphorylation sis of the placenta and liver [50–52]. HGF is also involvedin the development of epithelial tissues, including theof C-terminally clustered tyrosine residues [33–36]. Phos-

phorylation of these tyrosine residues recruits intracellu- kidney, lung, mammary gland, and teeth, as a mediator inepithelial–mesenchymal interactions for organogenesislar signaling molecules containing the src homology (SH)

domain, including Gab-1, phospholipase C-g (PLC-g), (discussed later in this article) [18, 53]. Concerning neu-roneal development, HGF supports the projection ofRas-GTPase activating protein (Ras-GAP), phosphati-

dylinositol 4,5-bisphosphate 3-kinase (PI-3 kinase), c-Src, motor neurons [54].Shp-2, Crk-2, and Grb-2 (Fig. 1B). Physiologically, HGF has an organotrophic role in the

Although the intracellular signaling pathways leading regeneration and protection of various organs, includingto specific or preferential activation of each biological the liver, lung, stomach, pancreas, heart, neurons, andresponse (that is, mitogenic, motogenic, morphogenic, kidney [16, 55]. HGF levels increase in tissues and bloodor anti-apoptotic) driven by HGF-Met receptor coupling in response to various acute injuries and diseases. Thehave yet to be fully defined, preferential activation of administration of HGF into laboratory animals has po-signaling molecules and induction of gene expression tent therapeutic effects on various models of acute andresponsible for activation of specific cellular responses chronic organ diseases [part of related publications, ex-are evident. Phosphotyrosine-dependent recruitment of cept for renal diseases; 48, 49, 56–76]. Likewise, HGFthe Grb-2/SOS complex activates Ras and subsequent has angiogenic activity for vascular endothelial cells andphosphorylation events, including extracellular signal- induces extensive blood vessels when administered intoregulated kinase (ERK). Activation of the Ras-ERK ischemic tissue [65, 70, 76, 77]. On the other hand, HGFpathway is required for cellular proliferation [33]. On regulates malignant behavior in various types of tumors,the other hand, the association and tyrosine phosphory- including invasion, metastasis, and tumor angiogenesislation of Gab-1, a docking protein that couples the Met [27, 29, 67]. Likewise, aberrant activation of the c-Metreceptor with multiple signaling proteins such as PI-3 receptor is associated with tumorigenesis and malignantkinase, PLC-g, Shp-2, and Crk-2, plays a definite role behavior of cancers [27, 29, 78]. The gain-of-functionin HGF-induced morphogenesis and cellular movement mutation in the c-met gene plays a determinant role in[36, 37]. The expression of Gab-1 in Madin-Darby canine hereditary and some sporadic papillary renal carcinomaskidney (MDCK) renal epithelial cells induces cell move- [79–81].ment and branching tubulogenesis [37]. The associationof Gab-1 with Shp-2 protein tyrosine phosphatase, but

ACTIONS OF HGF IN RENALnot PI-3 kinase and Crk-2, is essential for inducing epi-TISSUE ORGANIZATIONthelial branching tubulogenesis [36, 38]. Instead, activa-

Hepatocyte growth factor exerts mitogenic responsestion of PI-3 kinase and the Rho family GTPases (Rho,in renal epithelial cells derived from distinct regions andRac, Cdc42) plays a critical role in HGF-induced cellspecies, including rabbit and rat proximal tubular cellsmovement [39–42]. Rho GTPases regulate actin-related[82–84] and rat glomerular epithelial cells [84]. Figurecytoskeletal organization and contractive force for cell2A shows the effects of HGF and epidermal growthmovement and concomitant cell shape rearrangement.factor (EGF) on DNA synthesis of cultured rabbit proxi-Likewise, HGF induces tyrosine phosphorylation of fo-mal tubular cells [82]. HGF stimulates the proliferationcal adhesion kinase (FAK) [43, 44] and b-catenin [45, 46],

thereby enhancing the cell–ECM interaction and de- of renal epithelial cell lines, including a rat visceral glo-


merular cell line [85], proximal tubular cell lines [86],and a murine medullary collecting duct epithelial cell line[87]. Likewise, HGF exhibits mitogenic action on renalendothelial cells [88]. HGF has no apparent effect on ratand human mesangial cell proliferation [84, 88, 89] andis weakly mitogenic [89, 90], although mesangial cells doexpress the c-Met receptor [88–90]. HGF diminished ordecreased stress fibers, focal contacts, and extracellularfibronectin deposition in a murine mesangial cell culture,thereby suggesting a reduced cell–substratum interactionand enhanced cellular motility and remodeling in themesangial cell-related extracellular scaffold [89]. Like-wise, enhancement of cell motility in renal epithelial cellsclearly has been evidenced in MDCK renal epithelialcells [24, 25], and HGF stimulated Na,K-ATPase in arenal tubular cell line [86].

The indispensable role of tubular cells for renal func-tions depends on their multicellular architecture, that is,branching tubules, and formation of branching tubulo-genesis is involved in both renal regeneration and devel-opment. Montesano, Schaller, and Orci, using a model ofepithelial–mesenchymal interaction, first demonstratedthat MDCK renal epithelial cells undergo branching tu-bulogenesis in collagen gels in the presence of fibroblast-derived conditioned medium [91], and the fibroblast-derived epithelial morphogen proved to be HGF [92].Figure 2B shows the induction of branching tubulogen-esis by HGF in MDCK cells grown in a collagen gel.Other growth factors such as EGF, fibroblast growthfactor-1 (FGF-1), FGF-2, FGF-7, insulin-like growth fac-tor-I (IGF-I), IGF-II, and platelet-derived growth factor(PDGF) do not induce branching tubulogenesis, whereastransforming growth factor-b1 (TGF-b1) inhibits tubulo-genesis in MDCK cells [92, 93]. Further insight into theprocess of branching tubulogenesis reveals that branch-ing tubules formed by HGF in MDCK cells retain a well-defined apical-basolateral polarity [94] and that mem-brane type-matrix metalloproteinase plays an essentialrole in HGF-induced branching tubulogenesis [28]. Boweset al reported that HGF induces branching tubulogenesisof renal proximal tubular cells in primary culture [95].

Fig. 2. (A) Mitogenic action of HGF (d) and epidermal growth factorOther growth factors, including FGF-1, FGF-7, EGF, or (EGF; s) on cultured rabbit renal tubular cells. DNA synthesis of renal

tubular cells cultured in the absence or presence of HGF or EGF wasIGF-I, failed to induce this morphogenesis, however,measured. (B) Induction of branching tubulogenesis by HGF in MDCKcombinations of these growth factors induced branchingrenal epithelial cells grown in a collagen gel. Cells were grown in the

tubulogenesis [95]. These results indicate that morpho- absence or presence of 10 ng/mL HGF. (C) Potential roles of HGF inepithelial–stromal and endothelial–mesangial interactions in the kidney.genic signal transduction through HGF-Met is redun-

dantly achieved by a combination of multiple signals, co-operatively activated by sets of growth factors and theirreceptors. While HGF is not the sole molecule capable of

induces the ureteric bud to bud and branch, and theinducing branching tubulogenesis in renal tubular cells,ureteric bud, in turn, induces metanephric condensationit is definitely important for reconstructing the tubularand the mesenchymal to epithelial cell conversion [96, 97].architecture during renal development and regeneration.In the developing kidney, HGF is expressed in the meta-During renal development, a signal exchange betweennephric mesenchyme, and the Met receptor is expressedthe metanephric mesenchyme and the epithelial ureteric

bud plays a crucial role. The metanephric mesenchyme in the ureteric buds and in the epithelial cells of the


Fig. 2. (Continued)

nephron [98–100]. Neutralizing antibody to HGF inhib- apoptotic action of Bcl-2/Bcl-xL, and Bag-1 expressionited metanephric growth and morphogenesis in an organ in cells promotes the cell survival action of HGF [106].culture of embryonic kidneys [99, 100]. In addition, HGF In tubular regions of the adult kidney, HGF is ex-enhances differentiation of metanephric mesenchymal pressed in interstitial cells, presumably endothelial cellscells into epithelial cells, whereas anti-HGF antibody and macrophages [107–109], while in the glomerulus, mes-inhibits it, thereby indicating that HGF mediates the angial cells and endothelial cells express HGF [84, 86, 89,mesenchymal to epithelial conversion of the metanephric 102]. Collectively, in the kidney, HGF seems to act onmesenchyme [100, 101]. renal epithelial, endothelial, and mesangial cells through

Hepatocyte growth factor protects renal epithelial cells autocrine- or paracrine-related pathways (Fig. 2C).from apoptotic cell death [102–105], and the anti-apoptoticeffect of HGF in renal epithelial cells is mediated by the

HGF IN RENOTROPIC SYSTEMSinduction of Bcl-xL expression and the phosphorylationIn addition to biological activities of HGF on renalof Bad, thereby inactivating this pro-apoptotic protein.

cells, involvement of HGF in renal regeneration has beenIt is noteworthy that Bag-1, a partner of Bcl-2/Bcl-xL, isproposed based on findings that renal and plasma HGFspecifically associated with the c-Met receptor [106]. The

association of Bag-1 with Bcl-2/Bcl-xL enhances the anti- levels and c-Met receptor expression are regulated in


Fig. 3. Possible pathways mediated by HGF for renal regeneration in response to acute renal injury. (A) Following renal injuries, HGF expressionis up-regulated in stromal cells in the kidney and in distant intact organs such as the lung, liver, and spleen. The right upper panel shows inductionof HGF mRNA in the lung following unilateral nephrectomy (UN) in rats. (B) Regulation of c-Met receptor activation in noninjured and injuredtissues. Change in cell–cell contact or junctional communication due to tissue injury may possibly regulate c-Met receptor function, such that HGFexerts its biological activities in the injured tissue-specific manner.

response to renal injuries. A unilateral nephrectomy the kidney acting through paracrine and an autocrinemechanisms and HGF produced in distant organs actingmodel has been used to study renotropic systems in com-

pensatory renal regeneration. HGF mRNA and protein through an endocrine mechanism (Fig. 3A).The induction of HGF expression in distant intactlevels increase in the remaining kidney after unilateral

nephrectomy [110, 111]. Rapid increases in HGF mRNA organs suggests that a circulating factor(s) responsiblefor induction of HGF may exist in the blood of animalsand/or protein levels in the kidney and plasma were seen

in various types of acute renal injuries induced by the with organ injury. Two studies demonstrated the pres-ence of HGF-inducing factor in plasma or serum follow-administration of nephrotoxins such as HgCl2 and folic

acid, glycerol administration, renal ischemia, vitamin E ing the onset of acute organ injury. Plasma obtainedfrom laboratory animals with hepatic or renal injurydeficiency, and ureteral obstruction [107, 112–115]. Like-

wise, increases in blood HGF levels were noted in patients stimulated HGF expression in vivo and in vitro, and theHGF inducer was shown to be proteinous factor [123].with acute renal failure [116, 117] and with acute renal

rejection after renal transplantation [118]. Similarly, HGF levels in sera were remarkably increasedin patients with acute renal failure, and sera from patientsAn induction of HGF mRNA in the kidney following

renal injuries indicates that the kidney is one source of with acute renal failure—but not sera from healthy vol-unteers—strongly stimulated HGF production in mesan-HGF. In the kidney, stromal cells such as macrophages

and endothelial and mesangial cells express HGF [107, gial cells in culture [95].Although the identification of HGF inducers in the109]; thus, HGF seems to act through paracrine- and

autocrine-related pathways. On the other hand, HGF plasma or serum remains to be addressed, several knownmolecules are involved in regulating HGF expression.mRNA expression is up-regulated in distant intact or-

gans such as the lung, liver, and spleen, as well as the Among inflammatory mediators, interleukin-1 (IL-1),interferon-g, tumor necrosis factor-a, and prostaglandininjured kidney following acute renal injury, including

unilateral nephrectomy (Fig. 3A), HgCl2 administration, E1 (PGE1) and PGE2 strongly activate gene expressionof HGF [124–126]. Likewise, FGF-1, FGF-2, PDGF, hep-and folic acid administration [114, 119–121]. It is note-

worthy that the induction of HGF mRNA expression in arin-binding EGF-like growth factor (HB-EGF), EGF,and TGF-a induce HGF expression [127–130], whereasdistant noninjured organs was seen in cases of hepatic

and heart injuries [119–122]. These observations suggest TGF-b1 and angiotensin II strongly suppress the geneexpression of HGF [131–133]. Norepinephrine up-regu-that HGF increases in the blood circulation may be de-

rived from noninjured organs, as well as injured organs. lates HGF expression [134], whereas glucocorticoid neg-atively regulates HGF expression [131]. The induction ofTherefore, renotropic systems supported by HGF may

involve two distinct pathways: HGF locally produced in HGF by inflammatory mediators implicates its coopera-


tion with immune and regeneration/repair systems, while to two-chain HGF in injured organs. Since neutralizingantibody to HGF-activator inhibited processing to theregulation of HGF by adrenal hormones implicates its

involvement in neuroendocrine and regeneration systems. active HGF, this enzyme is likely to be involved in theinjured tissue-specific activation of HGF [139]. Takentogether, these biological actions of HGF seem to be

INJURED TISSUE-SPECIFIC ACTIVATION OFtightly regulated by distinct mechanisms involved in the

THE HGF–c-MET SYSTEMmodulation of receptor and ligand functions, such that

Given that HGF increases in the circulating blood, HGF exhibits biological actions in an injured tissue-spe-could it nonselectively target both injured and nonin- cific manner.jured tissues and cells? This may be an undesirable out-come, as there would be an overgrowth of noninjured

HGF IN CHRONIC RENAL FAILURE/tissues and cells. However, this is not the case. BindingRENAL FIBROSISof growth factors to their receptors induces down-regula-

tion of receptors because of endocytosis of the ligand- Progressive fibrosis in the kidney, liver, lung, heart,muscle, bone marrow, and skin is both a major cause ofreceptor complex. Thus, analysis of down-regulation

allows one to track ligand-dependent activation of growth suffering and death and an important contributor to thecost of health care, including hemodialysis. Dialysis mar-factor receptors. Analysis of the c-Met receptor in plasma

membranes of injured and noninjured tissues indicates ket estimates indicate that more than 400,000 patientsworldwide have undergone maintenance dialysis, andthat down-regulation of the c-Met receptor occurs in

injured but not in noninjured organs [135, 136]. Down- the number of patients with chronic renal disease is in-creasing.regulation of the c-Met receptor occurs in the kidney

(but not in other organs) after unilateral nephrectomy, Chronic renal disease, characterized by a progressiveloss of parenchyma cells and renal fibrosis, representswhile it occurs in only the liver after hepatic injury. While

the mechanisms by which HGF selectively activates the the morphological equivalent of end-stage chronic renaldisease and occurs independently of the primary under-c-Met receptor in injured tissue are unknown, we can

speculate about the possible mechanisms. In mature he- lying disorder. The intricate architecture and filtratingfunction of the kidney make it particularly vulnerablepatocytes in primary culture, HGF exerts mitogenic ac-

tion in a cell density-dependent manner. HGF potently to the consequences of fibrosis. Distinct lines of evidencepoint to a causal relation between overexpression ofenhances DNA synthesis of hepatocytes cultured at a

low cell density but does not do so in the case of a high TGF-b and the onset of glomerular and tubulointerstitialfibrosis [140–142]. Transgenic expression of TGF-b1 incell density [137]. Moreover, hepatocytes cultured at a

low cell density express a greater number of c-Met recep- mice leads to glomerulosclerosis and tubulointerstitialfibrosis [143–146]. Overexpression of TGF-b1 or TGF-b2tors than when cultured at a high cell density. The rate

of internalization and recycling of the c-Met receptors by intravenous injection or in vivo gene transfectionshowed that the kidney is highly susceptible to rapidon hepatocytes cultured at a low cell density was much

faster than that seen in the case of a high cell density fibrosis [147, 148]. Elevated expression of TGF-b wasnoted in animal models of renal fibrosis [108, 109, 149–[138]. These results suggest that cell–cell adhesion and

communication may regulate the function and expres- 152] and in patients with glomerulonephritis, diabeticnephropathy, and chronic allograft rejection [153–155].sion of the c-Met receptor, such that HGF exerts biologi-

cal activities in an injured tissue-specific manner (Fig. Biological neutralization of TGF-b1 with a proteoglycan(decorin) prevented the increased production of ECM3B). On the other hand, Liu et al found that c-Met

mRNA expression and c-Met protein were markedly in glomeruli [156].Biological actions of TGF-b are in accord with theincreased following injury to the kidney, where active

renal tissue repair/regeneration occurred, thereby sug- notion that overproduction of TGF-b is associated withthe onset of fibrotic disorders. TGF-b causes depositiongesting that local up-regulation of the c-Met receptor

may confer a specificity/susceptibility of HGF to renal of ECM proteins by simultaneously stimulating synthesisof most ECM proteins and the production of inhibitorstissue [114].

The other potential mechanism for injured tissue-spe- of matrix-degrading proteases [140]. For epithelial andendothelial cells, TGF-b induces growth arrest and in-cific activation of c-Met receptor may be associated with

proteolytic activation of single-chain pro-HGF to mature creases apoptotic cell death. TGF-b induces transdiffer-entiation of mesangial cells and renal tubular epithelialHGF, which occurs in an injured tissue-specific manner

[121]. Although HGF increases in the liver, kidney, lung, cells into a-smooth muscle actin (a-SMA)-positive myo-fibroblasts [157, 158]. Myofibroblasts play a definite roleand spleen in response to hepatic and renal injuries,

HGF remains as an inactive single chain in noninjured in the progression of renal fibrosis [159–161].Until recently, it remained unclear whether HGF isorgans, while a significant portion of HGF is converted


Fig. 4. Possible involvement of counterbalance between HGF and transforming growth factor-b (TGF-b) in the pathogenesis of chronic renalfailure/renal fibrosis. In the beginning of chronic injury, HGF expression is up-regulated, and the compensatory regenerative responses occur.Repetitive injury results in overexpression TGF-b, a potent fibrogenic cytokine that induces extracellular matrix (ECM) accumulation and epithelialand endothelial apoptosis. Since TGF-b suppresses HGF expression, HGF decreases in a reciprocal manner to the increase in TGF-b level duringthe progression of chronic renal failure.

associated with accelerating or preventing the progres- fibrosis and dysfunction. TGF-b expression and ECMaccumulation were increased concomitantly with in-sion of renal fibrosis. However, recent studies clearly

showed that HGF has a role in protecting the nephrotic creases in tubular apoptosis and with decreases in tubularproliferation. In contrast, the administration of HGFkidney from fibrosis [108, 109, 152, 162]. In the ICR

strain-derived glomerulonephritis (ICGN) mice, glomer- strongly suppressed TGF-b expression and preventedthe onset of renal fibrosis and chronic renal failure. Theseular injury is detectable from 3 weeks postnatally, while

renal dysfunction occurs from 12 to 14 weeks, a dysfunc- findings mean that the reciprocal balance between TGF-band HGF is closely associated with the pathogenesis andtion that coincides with tubular destruction and tubulo-

interstitial fibrosis. Because renal dysfunction in patients progression of renal fibrosis and that HGF plays a rolein protecting the kidney from fibrotic changes. In addi-with glomerular disease shows a better correlation with

tubulointerstitial fibrosis than with glomerulosclerosis, tion to the overexpression of TGF-b, a decrease in renalHGF expression may be responsible for the occurrencethe ICGN mouse offers an appropriate model for patho-

physiological studies on human chronic renal disease. of chronic renal disease (Fig. 4).It is noteworthy that a similar reciprocal change in theIn ICGN mice, the expression and the renal level of

TGF-b increase during progression of glomerular and expression of TGF-b and HGF was also noted during theonset of tubulointerstitial fibrosis caused by unilateraltubulointerstitial fibrosis. Renal TGF-b levels correlate

fairly well with accumulation of type I collagen and fi- ureter-ligated obstruction in mice [109]. Likewise, sup-pressive effects of endogenous HGF on chronic renalbronectin, and tubular apoptosis, whereas there is an in-

verse correlation with proliferation of tubular cells [108]. injury and renal fibrosis were demonstrated following5/6 nephrectomy in rats [162]. The administration ofOn the other hand, HGF levels in the kidney are initially

higher than normal at the early stage of glomerulone- neutralizing anti-HGF antibody decreased the glomeru-lar filtration rate and increased renal fibrosis, indicatingphritis, whereas there is a gradual decrease during pro-

gression of renal fibrosis, and the renal HGF level is that endogeneous HGF plays a role in protecting thekidney from chronic renal injury and renal fibrosis. Al-lower than that in normal kidney at advanced stages of

the disease (Fig. 4). Thus, the renal HGF level correlates though involvement of the TGF-b–versus–HGF counter-balance in the onset of chronic renal failure has yet towith a decrease in tubular proliferation and inversely

correlates with increase in the renal TGF-b level, ECM be noted in patients, this reciprocal expression patternwas noted in the livers of patients with a chronic hepaticaccumulation, and tubular apoptosis. To address the

involvement of HGF in progression of renal fibrosis, disease [163, 164]. The increase in blood HGF levels inpatients with “chronic” renal failure is much less thanneutralizing anti-HGF antibody or recombinant HGF

was administered to ICGN mice. Neutralization of en- that in patients with “acute” renal failure [116, 165].Given that a reciprocal balance between TGF-b anddogenous HGF strongly accelerated progression of renal


Fig. 5. Preventive effect of HGF on acuterenal failure induced by administration of cis-platin (A) or HgCl2 (B). Acute renal failurewas induced by cisplatin (15 mg/kg bodyweight; A) or HgCl2 (7 mg/kg body weight;B). Mice were injected with HGF (250 mg/kgbody weight) at 0.5 hours prior to administra-tion of cisplatin or HgCl2 and 6, 12, 24, 36, 48and 72 hours or 6, 12, 24, 36, and 48 hoursafter the administration of cisplatin or HgCl2,respectively. BUN (j) and serum creatinine( ) at 96 (cisplatin) or 72 hours (HgCl2) weremeasured. Each value represents the mean 6SD [174].

HGF regulates the pathology of chronic renal disease, mice. In transgenic mice expressing HGF under controlhow this reciprocal balance is achieved and how supple- of the metallothionein promotor (MT-HGF transgenicmentation of exogenous HGF protects the kidney from mice), the mice developed tubular hyperplasia, glomeru-chronic renal fibrosis and dysfunction deserve attention. losclerosis, and polycystic disease [169]. The same miceFirst, TGF-b1 strongly suppresses expression of HGF also developed tumors of diverse origin, including themRNA [131–133], and this TGF-b1–induced suppression mammary gland, skin, and liver [170]. In contrast, inof HGF expression explains why the overexpression of transgenic mice in which the HGF gene is expressedTGF-b is associated with a decreased renal HGF expres- under control of a tissue-specific promoter, tumors didsion. In the promoter region of the HGF gene, there is not develop. Transgenic mice expressing HGF under ana TGF-b inhibitory element involved in TGF-b–induced albumin promoter (Alb-HGF transgenic mice) had atranscriptional inhibition [166, 167], and TGF-b inhibits greatly increased potential for liver regeneration aftertranscription of the HGF gene [168]. On the other hand, partial hepatectomy, but hepatocellular carcinoma didhow exogenous HGF suppresses renal TGF-b levels has not occur [171]. Keratinocyte-specific transgenic expres-yet to be determined. HGF might possibly inhibit tran- sion of HGF affects melanocyte development, leadingscription of the TGF-b gene directly through the c-Met to melanocytosis, but tumors did not occur, even fromreceptor, or the number of TGF-b–positive cells in the the skin [172]. Likewise, transgenic mice expressing HGFkidney may be decreased. TGF-b and HGF are counter- in pancreatic b cells did not develop tumors, and theacting in many multipotent biological actions. TGF-b mice were resistant to the diabetogenic effects of strepto-induces growth arrest and/or apoptosis in renal tubular zotocin [173]. Abundant expression of HGF in variouscells and endothelial cells, but HGF exhibits mitogenic tissues and greatly increased systemic HGF levels fromand anti-apoptotic activities in these cell types. HGF

early developmental stages in MT-HGF transgenic miceinduces branching tubulogenesis in renal epithelial cells,might affect differentiation, maturation, or epithelial re-while inhibition is seen with TGF-b. HGF stimulates ornewal, which results in renal pathology and tumor devel-induces proteases involved in the breakdown of ECMopment in various tissues. In contrast, in vivo studiesproteins in several types of cells, including MT1-MMP,analyzing the therapeutic potential of HGF in relevantuPA, and some matrix metalloproteases (MMPs) [26–29].models for various diseases found no side effects thatIn contrast, TGF-b strongly stimulates the synthesis ofwould limit the therapeutic usage of HGF or the HGFECM proteins and the production of inhibitors of prote-gene [48, 49, 56–76, 108, 109, 152, 174–177]. Therefore,ases involved in ECM breakdown [140]. Consistently,abundant expression of the HGF gene or abundant ad-HGF increased the expression of MMP-9, whereas HGFministration of HGF in which HGF levels reach muchdecreased the expression of tissue inhibitors of matrixhigher levels than are physiologically or pharmacologi-metalloptoteinase-1 (TIMP-1) and TIMP-2 in humancally effective for a long period may potentially cause aproximal renal tubular cells in culture [162].pathology, including renal pathology.

INVOLVEMENT OF ABERRANT HGFPOTENTIAL THERAPEUTIC APPLICATIONSEXPRESSION IN PATHOLOGY

Based on the renotropic and antifibrogenic actions ofInvolvement of an abundant expression of HGF inpathology has been implicated from studies on transgenic HGF, the potential application of HGF for the treatment


of renal diseases has been tested in various experimentalmodels. In a clinical setting, acute renal failure is oftencaused by nephrotoxic drug administration (for example,cisplatin, cyclosporine A, tacrolimus, and antibiotics)and renal ischemia. Administration of cisplatin causedacute renal failure in mice, whereas prophylactic admin-istration prevented histologic destruction of renal tu-bules and strongly suppressed the onset of acute renaldysfunction (Fig. 5) [174]. Similarly, HGF prevented thehistologic destruction of renal tissue and the onset ofacute renal dysfunction caused by HgCl2 administration,while it enhanced regeneration of tubular epithelial cells[174]. Preventive effects of HGF in cases of acute tubularinjury and renal dysfunction were also seen in case ofcyclosporine A and tacrolimus (FK506) [176, 177]. Like-wise, compared with control rats, rats administered HGFpostischemia had better renal function, reduced mortal-ity, and a lesser degree of histologic injury when renalischemia was induced in rats by bilateral artery occlusion[175]. All of these results suggest that HGF can be testedfor treatment of patients with acute renal failure or forprophylaxis of acute renal failure potentially caused byadministration of nephrotoxic drugs.

Preventive actions of HGF on acute renal injury couldbe potentially extended to chronic allograft nephropathyafter renal transplantation [178, 179]. Chronic allograftnephropathy, characterized by renal fibrosis and dys-function, often develops years after renal transplantationand is a major cause of graft loss. In an experimentalmodel of chronic allograft nephropathy in rats, HGF wasadministered daily for four weeks following engraftment.In control rats without HGF-treatment, allografts showedsevere structural damage within one week. After a periodof quiescence, macrophage infiltration, elevated TGF-b1expression, and myofibroblasts were seen at 16 weeks.

Fig. 6. Therapeutic effect of HGF on chronic renal failure/renal fibrosisAt 32 weeks, renal fibrosis and dysfunction occurred, and in ICGN mice. (A) Changes in TGF-b, collagen accumulation, tubularthe mortality rate was 50%. In contrast, there was little apoptosis, and tubular proliferation by HGF administration in kidneys

of ICGN mice, as determined by enzyme immunoassay (TGF-b) andearly injury and no later renal fibrosis or dysfunction, andimmunohistochemical analysis (collagen type I, apoptosis, and BrdU-all HGF-treated rats survived. Consistently, macrophage uptake). (B) Changes in BUN and serum creatinine (SCr) levels, without

infiltration and overexpression of TGF-b1 in the kidney (s) or with (d) HGF-treatment. When BUN levels reached 40 mg/dL,HGF (500 mg/kg) or saline alone was given daily for 28 days [108, 152].were suppressed in HGF-treated animals. Since acute

ischemic injury during renal transplantation is associatedwith the onset of chronic allograft nephropathy [180,181], the effects of HGF on ischemic injury might prevent therapeutic efficacy of HGF in murine models of chronicthe onset of chronic allograft nephropathy. renal disease and tubulointerstitial fibrosis was remark-

Understanding the molecular and cellular mechanisms able [108, 109, 152]. In ICGN mice, recombinant HGFleading to chronic renal disease has progressed; however, was administered for four weeks during middle- to end-many chronic renal diseases remain incurable. As de- stage chronic renal disease.scribed previously in this article, endogenous renal HGF In control mice not given HGF, molecular and cellularlevels decrease along with progression of renal fibrosis, events leading to end-stage chronic renal disease pro-and neutralization of endogenous HGF accelerates the gressed during this period. Renal TGF-b levels, the num-progression of renal fibrosis toward end-stage pathology. ber of a-SMA-positive myofibroblasts, type I collagenTherefore, supplemental administration of HGF to com- and fibronectin accumulation and the number of tubularpensate for decreased HGF levels may be therapeutic apoptosis increased, whereas the number of proliferating

tubular cells decreased. In contrast, in mice treated within cases of renal fibrosis and chronic renal failure. The


Fig. 7. Putative mechanism for therapeutic effects of HGF on chronic renal failure/renal fibrosis. The supplement of HGF suppresses TGF-bexpression and enhances remodeling of renal tissues, including ECM degradation and epithelial and endothelial cell proliferation in fibrotic kidneys.HGF may prevent cell death in epithelial and endothelial cells.

HGF, expression of TGF-b and PDGF, ECM accumula- remarkably increased in the cirrhotic liver, whereas thetion, and the number of myofibroblasts and tubular apo- administration of HGF or the HGF gene induced theptosis decreased, whereas the number of regenerating remodeling of fibrotic/cirrhotic tissue toward a normaltubular cells increased (Fig. 6A). Consistent with these hepatic structure with an accompanying marked de-changes, the beneficial effects of HGF on the clinical crease in hepatic TGF-b expression. Although an associ-outcome were apparent as decreases in levels of serum ation of TGF-b–versus–HGF counterbalance in patho-creatinine, blood urea nitrogen (BUN), and urine albu- genesis and therapeutics of fibrotic disorders was firstmin, and as a diminution in histologic renal injury (Fig. deduced from a murine model of chronic renal disease/6B) [152]. It should be emphasized that serum creatinine, renal sclerosis, it is tempting to hypothesize that theBUN and urine albumin levels, and histologic renal in- counterbalance between TGF-b and HGF has a determi-jury in mice treated with HGF were less than such events nant role in the pathogenesis and therapeutics of a vari-seen at the start of HGF administration. These results ety of fibrosis-related diseases.indicate that treatment with HGF has therapeutic effectsin cases of chronic renal disease, rather than the HGF

CONCLUSION AND PERSPECTIVESsupplements merely retarding or inhibiting the progres-The renotropic system underlies the vital ability of thesion of chronic renal disease (Fig. 7).

kidney to regenerate in response to injury or partialIn addition to renal fibrosis in ICGN mice, the adminis-resection of the kidney. Several growth factors play rolestration of HGF attenuated tubulointerstitial fibrosis, de-in renotropic systems [104, 183]; however, the specificcreased TGF-b expression and tubular apoptosis, androle of each growth factor in renotropic systems has yetincreased tubular proliferation/regeneration followingto be fully clarified. HGF, a renotropic growth factor,unilateral ureter-ligated obstruction in mice [109]. Uni-mediates epithelial–stromal and endothelial–mesangiallateral ureter-ligated obstruction has been widely used asinteractions for regeneration and maintenance of thea model to study the pathogenesis of tubulointerstitial fi-kidney. In response to acute renal injury, the expressionbrosis. In addition, HGF inhibited the cyclosporine A- orof HGF increases and HGF exerts renotropic actions.tacrolimus-induced endothelin-1 release from culturedDuring progression of chronic renal failure/fibrosis, HGFrabbit proximal tubular cells [182]. Endothelin, which isexpression in the kidney decreases to a level much lowerinvolved in the pathogenesis of acute and chronic renalthan normal. The dominant expression of TGF-b overfailure, mediates the nephrotoxic side effects of cyclo-HGF is associated with the progression of chronic renalsporine A and tacrolimus. Moreover, it is noteworthyfailure. HGF has preventive and therapeutic effects inthat HGF plays a role in protecting the liver and lungscases of acute and chronic renal failure by enhancingfrom liver cirrhosis and lung fibrosis in laboratory ani-

mals [57, 59, 61, 63, 71, 74]. The expression of TGF-b1 the reorganization of renal tissue following injuries and


2. Austin H III, Goldin H, Preuss HG: Humoral regulation offibrosis. HGF may participate in remodeling and regen-renal growth. Nephron 27:163–170, 1981

erative processes of renal tissue not only by enhancing 3. Nakamura T, Nawa K, Ichihara A: Partial purification and char-acterization of hepatocyte growth factor from serum of hepatec-cell growth, but also by promoting the spatial arrange-tomized rats. Biochem Biophys Res Commun 122:1450–1459, 1984ment of parenchymal cells into organized tissue structures.

4. Russell WE, McGowan JA, Bucher NLR: Partial characteriza-To understand renotropic systems better, the ques- tion of hepatocyte growth factor from rat platelets. J Cell Physiol

119:183–192, 1984tions of how renal injury is recognized by renal cells and5. Nakamura T, Teramoto H, Ichihara A: Purification and charac-how the occurrence of injury leads to specific induction

terization of a growth factor from rat platelets for mature paren-of renotropic growth factors remain to be addressed. chymal hepatocytes in culture. Proc Natl Acad Sci USA 83:6489–

6493, 1986HGF increases in the blood circulation and in distant6. Nakamura T, Nawa K, Ichihara A, et al: Purification and subunitintact organs, as well as in the kidney, in response to

structure of hepatocyte growth factor from rat platelets. FEBSrenal injury. Molecules responsible for the induction of Lett 224:311–318, 1987

7. Gohda E, Tsubouchi H, Nakayama H, et al: Purification andHGF and how HGF is involved in regulation of otherpartial characterization of hepatocyte growth factor from plasmagrowth factors will also need further attention. Likewise,of a patient with fulminant hepatic failure. J Clin Invest 88:414–

the manner in which HGF exerts biological actions spe- 419, 19888. Zarnegar R, Michalopoulos GK: Purification and biologicalcifically in the injured kidney requires further study. Reg-

characterization of human hepatopoietin A, a polypeptide growthulation of the c-Met receptor function may be involved factor for hepatocytes. Cancer Res 49:3314–3320, 1989in this issue. Thus, renotropic systems could be achieved 9. Nakamura T, Nishizawa T, Hagiya M, et al: Molecular cloning

and expression of human hepatocyte growth factor. Nature 342:by time-dependent and cell type-specific activation of440–443, 1989ligand-receptor systems in growth factor networks that 10. Tashiro K, Hagiya M, Nishizawa T, et al: Deduced primary

orchestrate reconstruction processes of the injured kid- structure of rat hepatocyte growth factor and expression of themRNA in rat tissues. Proc Natl Acad Sci USA 87:3200–3204, 1990ney. A better comprehension of these issues will provide

11. Miyazawa K, Shimomura T, Kitamura A, et al: Molecular cloninga paradigm concerning tissue regeneration in biological and sequence analysis of the cDNA for a human serine proteasedefense systems. responsible for activation of hepatocyte growth factor. Structural

similarity of the protease precursor to blood coagulation factorPreclinical and clinical trials of HGF or HGF geneXII. J Biol Chem 268:10024–10028, 1993therapy for treatment of patients with renal diseases can 12. Naldini L, Vigna E, Bardelli A, et al: Biological activation of

be designed if a careful evaluation of the side effects is pro HGF (hepatocyte growth factor) by urokinase is controlledby a stoichiometric reaction. J Biol Chem 270:603–611, 1995made. The first clinical trials of HGF gene therapy for

13. Nakamura T: Structure and function of hepatocyte growth factor.patients with arteriosclerosis obliterans, myocardial in- Prog Growth Factor Res 3:67–85, 1991farction, and liver cirrhosis are in the planning stage. 14. Zarnegar R, Michalopoulos GK: The many faces of hepatocyte

growth factor: From hepatopoiesis to hematopoiesis. J Cell Biol129:1177–1180, 1995

ACKNOWLEDGMENTS 15. Matsumoto K, Nakamura T: Emerging multipotent aspects ofhepatocyte growth factor. J Biochem 119:591–600, 1996The work in the authors’ laboratory was supported by Research

16. Matsumoto K, Nakamura T: Hepatocyte growth factor (HGF)Grants from the Ministry of Education, Science, Sports, and Cultureas a tissue organizer for organogenesis and regeneration. Biochemof Japan, the Ministry of Health and Welfare of Japan, and by aBiophys Res Commun 239:639–644, 1997Research Grant from the Osaka Kidney Foundation. We are grateful

17. Kopp JB: Hepatocyte growth factor: Mesenchymal signal for epi-to M. Ohara for helpful comments.thelial homeostasis. Kidney Int 54:1392–1393, 1998

18. Balkovets DF, Lipschutz JH: Hepatocyte growth factor and theReprint requests to Toshikazu Nakamura, Ph.D., Biomedical Re-kidney: It is just not for the liver. Int Rev Cytol 186:225–260, 1999search Center, Osaka University Graduate School of Medicine, 2-2

19. Gustavo A, Hoeflich A, Jehle PM: Hepatocyte growth factorYamada-oka, Suita, Osaka 565-0871, Japan.in renal failure: Promise and reality. Kidney Int 57:1426–1436,E-mail: [email protected]

20. Furlong RA, Takehara T, Taylor WG, et al: Comparison ofbiological and immunochemical properties indicates that scatter

APPENDIX factor and hepatocyte growth factor are indistinguishable. J CellSci 100:173–177, 1991Abbreviations used in this article are: a-SMA, a-smooth muscle 21. Konishi T, Takehara T, Tsuji T, et al: Scatter factor from humanactin; BUN, blood urea nitrogen; ECM, extracellular matrix; EGF,embryonic fibroblasts is probably identical to hepatocyte growthepidermal growth factor; ERK, extracellular signal-regulated kinase; factor. Biochem Biophys Res Commun 180:765–773, 1991FAK, focal adhesion kinase; FGF-1, fibroblast growth factor-1; FK506, 22. Weidner KM, Arakaki N, Hartmann G, et al: Evidence for

tacrolimus; HB-EGF, heparin binding-epidermal growth factor; HGF, identity of human scatter factor and human hepatocyte growthhepatocyte growth factor; IGF, insulin-like growth factor; MDCK, factor. Proc Natl Acad Sci USA 88:7001–7005, 1991Madin-Darby canine kidney; MMP, matrix metalloprotease; PDGF, 23. Stoker M, Perryman M: An epithelial scatter factor released byplatelet-derived growth factor; PGE, prostaglandin E; PI-3, phosphati- embryo fibroblasts. J Cell Sci 77:209–223, 1985dylinositol-5-bisphosphate 3-kinase; PLC-g, phospholipase C-g; Ras- 24. Gherardi E, Gray J, Stoker M, et al: Purification of scatterGAP, Ras-GTPase activating protein; SH, src homology; TGF-b, trans- factor, a fibroblast-derived basic protein that modulates epithelialforming growth factor-b; uPA, urokinase-type plasminogen activator. interaction and movement. Proc Natl Acad Sci USA 86:5844–5848,

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Hepatocyte growth factor: Renotropic role and potential therapeutics for renal diseases