Kidney International, Vol. 57 (2000), pp. 1426–1436

PERSPECTIVES IN BASIC SCIENCE

Hepatocyte growth factor in renal failure: Promise and reality

GUSTAVO A. VARGAS, ANDREAS HOEFLICH, and PETER M. JEHLE

Department of Internal Medicine II, Division of Nephrology, University of Ulm, Ulm, and Institute of Molecular AnimalBreeding, Gene Center, Munich, Germany

Hepatocyte growth factor in renal failure: Promise and reality. possible therapeutic applications of hepatocyte growthCan science discover some secrets of Greek mythology? In the factor (HGF) and its receptor, c-met [3–5].case of Prometheus, we can now suppose that his amazinghepatic regeneration was caused by a peptide growth factorcalled hepatocyte growth factor (HGF). Increasing evidence HEPATOCYTE GROWTH FACTOR/SCATTERindicates that HGF acts as a multifunctional cytokine on differ- FACTOR STRUCTURE AND SYNTHESISent cell types. This review addresses the molecular mechanisms

The biological features of HGF are summarized inthat are responsible for the pleiotropic effects of HGF. HGFTable 1. Previous studies described several mitogenic andbinds with high affinity to its specific tyrosine kinase receptormotogenic polypeptides that were identified later as HGFc-met, thereby stimulating not only cell proliferation and differ-

entiation, but also cell migration and tumorigenesis. The three [6–9]. Independently, the existence of a polypeptide se-fundamental principles of medicine—prevention, diagnosis, creted by embryonic fibroblasts was reported that promotesand therapy—may be benefited by the rational use of HGF. In the scattering of Madin-Darby canine kidney (MDCK)renal tubular cells, HGF induces mitogenic and morphogenetic and other epithelial cells by paracrine mechanismsresponses. In animal models of toxic or ischemic acute renal

[10–12]. This polypeptide was named scatter factor (SF)failure, HGF acts in a renotropic and nephroprotective manner.[13] and was later on identified as HGF [14–18]. Simulta-HGF expression is rapidly up-regulated in the remnant kidneyneously, fibroblast tumor cytotoxic factor (F-TCF) [19]of nephrectomized rats, inducing compensatory growth. In aand the broad spectrum mitogen produced by lung fi-mouse model of chronic renal disease, HGF inhibits the pro-

gression of tubulointerstitial fibrosis and kidney dysfunction. broblasts [20] were also found to be identical to HGF.Increased HGF mRNA transcripts were detected in mesenchy- The human HGF gene is localized on chromosome bandsmal and tubular epithelial cells of rejecting kidney. In trans- 7q11.2-21 [14]. The HGF gene promoter contains posi-planted patients, elevated HGF levels may indicate renal rejec- tive and negative regulatory elements and is highly con-tion. When HGF is considered as a therapeutic agent in human

served among human and rodent species [21]. Nativemedicine, for example, to stimulate kidney regeneration afterHGF is secreted as an inactive precursor (pro-HGF),acute injury, strategies need to be developed to stimulate cellwhich is converted to the active form after extracellularregeneration and differentiation without an induction of tumor-

igenesis. proteolysis by several activators [22–25] and in responseto tissue injury [26]. HGF activation could be inhibitedby a specific serine protease inhibitor [27].

It has been suggested that HGF, macrophage stimulat-Growth factors are involved in multiple responses such ing protein (MSP; a growth factor with biological effects

as cell proliferation, differentiation, and motility mediat- similar to HGF), apolipoprotein-a, and plasminogen haveing their effects via receptor tyrosine kinases [1, 2]. The evolved from a common ancestral gene [28, 29]. Twotype of response triggered depends on receptors and truncated variants of HGF containing the N-terminalligands that are differentially expressed by various cell region and the first (HGF/NK1) or the first and thetypes. This review focuses on the structure, function, and second (HGF/NK2) kringle domains are generated by

alternative splicing. NK2 behaves as an HGF antagonist[30]. NK1 is derived from a 2.2 kb transcript [4] and isable to exhibit agonistic and antagonistic actions [30–33].In hepatocytes, NK1 acts primarily as an HGF antagonistKey words: growth factors, HGF, cell proliferation, tumorigenesis,

nephroprotection, renotropic growth factor. [34] but elicits an agonistic response in the presenceof heparin [35]. NK1 transgenic mice reveal the typicalReceived for publication June 29, 1999phenotype of HGF transgenic mice, underscoring its ago-and in revised form October 18, 1999

Accepted for publication November 2, 1999 nistic action in vivo [36]. A shorter synthetic HGF vari-ant, HGF/NK4, can act as an antagonist [37]. 2000 by the International Society of Nephrology

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Vargas et al: HGF in renal failure 1427

Table 1. Synopsis on biologic features of hepatocyte Table 2. Synopsis on biologic features of c-metgrowth factor (HGF)

Polypeptide features of c-met• product of the c-met proto-oncogeneSynonymous polypeptides

• fibroblast tumor cytotoxic factor (F-TCF) • synonymous polypeptides not known• 190 kD precursor• hepatocyte growth factor (HGF)

• hepatopoietin A • N-glycosylated mature protein• two disulfide-linked subunits• hepatotropin

• scatter factor (SF) a-chain, 50 kD, extracellular locationb-chain, 145 kD, extracellular, transmembrane and intracellularRelated polypeptides

• apolipoprotein (a) two major isoforms differing by a 47-aa segment in the juxta-membrane domain• blood coagulation factor XIIa

• macrophage-stimulating protein (MSP) single noninterrupted tyrosine kinase domain in the b-chainRelated polypeptides• plasminogen

Biologic effects • Ron tyrosine kinase receptor (ligand MSP)• Sea tyrosine kinase receptor• mitogen

• morphogen c-met gene localization• human chromosome 7, bands 7q21-q23• motogen

• inductor of tubulogenesis Biologic function• receptor unique for HGF• promotor of invasiveness

HGF gene localization c-met expression• almost all epithelia (e.g., kidney, liver, stomach, small intestine,• human chromosome 7, bands 7q11.2-q21

Polypeptide characteristics brain, breast)• endothelial cells• monomeric inactive precursor (pro-HGF)

• heterodimeric form (a/b-chain) after proteolytic cleavage (728 aa) • increased expression in several carcinoma• various isoforms (truncation, alternative splicing)• four kringle domains• one inactive serine protease domain• four potential glycosylation sites• heparin and glycosaminoglycans binding sites A specific Tyr at position 1356 in the C-terminal tail is

HGF expressionneeded for cell motility and morphogenesis [57]. Heparin• during organ development (e.g., kidney, liver, trophoblast)

• in adult life in tissue of mesodermal origin (e.g., fibroblasts, blood or similar extracellular matrix compounds can modulatemononuclear cells, platelets) HGF binding and action [58, 59]. Heparin-like molecules

can stabilize HGF oligomers and enhance the mitogenicpotency, probably by facilitating c-met receptor dimer-ization and activation [60], whereas heparan sulfate pro-

HEPATOCYTE GROWTH FACTOR RECEPTOR teoglycans act as negative modulators [61].BINDING AND SIGNALING

The HGF receptor is the product of the c-met proto-EXPRESSION OF HEPATOCYTE GROWTHoncogene [38]. A synopsis on the biological features ofFACTOR AND c-met AND BIOLOGICAL EFFECTSc-met is given in Table 2. The c-met product is a tyrosine

Hepatocyte growth factor is expressed in tissues ofkinase receptor [39–43] with two disulfide-linked sub-mesodermal origin [62], whereas c-met is expressed inunits and a single noninterrupted kinase domain sharingepithelia, including liver and kidney [63], and in severalhomology with the src family of tyrosine kinases (Fig. 1).human carcinomas [64]. Steroid hormones, cytokines [tu-The c-met tyrosine protein kinase oncogene family ismor necrosis factor-a (TNF-a), interleukin (IL)-1, IL-6],related to cell invasiveness and comprises v-ros, the insu-and basic fibroblast growth factor (bFGF) regulate HGFlin-like growth factor (IGF)-I receptor, the 220 kD SEXand c-met expression [5, 65, 66]. According to the find-protein, Ron (MSP receptor), and Sea (sarcoma, erythro-ings in double transgenic HGF/transforming growth fac-blastosis, and anemia; unknown ligand) [44–49]. Ron andtor (TGF)-a mice, HGF produces a partially inhibitorySea can induce the same biological effects as c-met [47].effect on hepatocellular carcinogenesis induced by TGF-aAfter HGF binding and subsequent ligand-induced re-[67]. Furthermore, HGF can reverse the arrest on cellceptor dimerization, c-met is activated by autophosphory-growth induced by TGF-b [68], whereas TGF-b waslation (Fig. 1A) [16, 39, 41, 43, 50–52]. The principal siteshown to enhance the motogenic effects of epidermalfor autophosphorylation is located in the kinase domaingrowth factor (EGF) but not HGF [69]. EGF can nega-at Tyr 1235, which together with Tyr 1230 and Tyr 1234,tively modulate HGF-induced cell migration [70]. In con-comprises a common “three tyrosine” motif that is con-trast, the HGF-induced increase in DNA synthesis inserved in the insulin and platelet-derived growth factorhepatocytes of HGF-transgenic mice is intensified by(PDGF) receptor tyrosine kinases [53]. The phosphory-EGF or insulin, and the growth inhibitory effects oflation of Ser 985 [54] and a protein phosphatase [55] canTGF-b are depressed [71].negatively modulate c-met kinase activity. Experiments

Besides its renotropic action (vide infra), HGF exertswith receptor chimeras showed that c-met is the firstdownstream effector in the HGF signaling cascade [56]. pleiotropic biological effects on different cell types. At

Vargas et al: HGF in renal failure1428

Table 3. Role of HGF/c-met in kidney

Organogenesis• HGF or c-met knockout mice die in utero before any kidney

abnormality appearsIn vitro effects

• increase of DNA synthesis in kidney epithelial cells• scattering• invasiveness in collagen cells

In vivo effects• promotes the recovery of renal function after

ischemiaunilateral nephrectomychemical-induced renal damage

In human kidney disease• mutations in c-met are associated with hereditary papillary renal

carcinoma• c-met is increased in most of the renal carcinomas• possible link between HGF overexpression and renal cysts• possible association between c-met up-regulation and diabetic

renal hypertrophy

least some of the biological effects of HGF are due toinhibition of apoptosis [72, 73]. HGF is a potent mitogenfor hepatocytes and is crucial for liver development [74–76]. Transgenic mice expressing HGF under the controlof the albumin promoter performed liver regenerationtwo times faster than normal mice [77], whereas tumorsof diverse origin were found in HGF transgenic miceunder the control of the metallothionein promoter [78].On the other hand, in c-myc/HGF double transgenicmice, hepatic tumorigenesis induced by c-myc is pre-vented by HGF [79]. HGF-expressing fibroblasts preventthe onset of acute liver damage induced by CCl4 or bacte-rial lipopolysaccharide when transplanted into the spleenof rats [80]. Elevated HGF levels have been reportedafter partial liver resection, acute or chronic hepatitis,and fulminant liver failure [81, 82]. In acute hepatitis,serum HGF levels are approximately twofold highercompared with controls [83].

HEPATOCYTE GROWTH FACTOR, c-met, ANDTHE KIDNEY

Fig. 1. Molecular structure of the hepatocyte growth factor (HGF)The role of HGF and c-met in the kidney is summa-receptor c-met (A) and signal transduction (B). (A) The c-met product

(left) is a tyrosine kinase receptor of 190 kD with two disulfide-linked rized in Table 3. During perinatal kidney developmentsubunits, a 50 kD extracellular a-chain (a) and a 145 kD b-chain (b). in rats, diverse receptor tyrosine kinases and growthHGF binding induces receptor dimerization (middle) and autophosphory-

factors are expressed or activated including c-met andlation (right). (B) After autoposphorylation in the kinase domain of c-met (Tyr1234, Tyr1235; indicated as Y in the white box), a downstream HGF [84]. In mouse metanephros at embryonic day 11,located multifunctional docking site (Tyr1349, Tyr1356) in the C-terminal

HGF is expressed primarily in the mesenchyme, whereasdomain mediates the signal to multiple transducers, including PI3 ki-nase, the Grb2/Sos/Ras complex, the IRS-like multiadaptor protein c-met is found also in the ureteric bud [85]. An importantGab-1, phospholipase-g, and probably Src. The pleiotropic effects of role of HGF during branching morphogenesis of theHGF are mediated via different signaling pathways, which may differ

ureteric bud has been suggested by several cell culturein various cell types.studies [85, 86]. HGF stimulates epithelial differentiationof metanephric mesenchymal cells [87]. The formationof HGF/SF-induced branching tubules in MDCK cellscultured in collagen gels is connected with the inductionof membrane type 1 matrix metalloproteinase [88]. At

Vargas et al: HGF in renal failure 1429

ing is based on the ability of HGF to inhibit junctionalcommunications, to enhance proteolysis of connexin 43[96], and to change the phosphorylation patterns of junc-tional molecules, thereby increasing their stability [97].In MDCK cells transformed with SV40 large T antigen,scattering is specifically triggered via inactivation of reti-noblastoma protein inducing an HGF autocrine loop[98]. In renal epithelial cells, the ectopic overexpressionof HGF is able to up-regulate the level of c-met and tostimulate cell scattering [99].

The pleiotropic effects of HGF are mediated via differ-ent signaling pathways, which may show differences invarious cell types. In all cases, a multifunctional dockingsite (Tyr at position 1349 and 1356 in the C-terminaldomain) mediates the signal of activated c-met receptorsto multiple transducers (Fig. 1B), including PI3 kinase,the Grb2/Sos/Ras complex, the insulin receptor substrate(IRS)-like multiadaptor protein Gab-1, and probably Src[100–102]. It is important to note that c-met–mediatedbiological effects can be dissected on the basis of differ-ent signaling requirements [100]. In MDCK cells, HGF-induced cell scattering is dependent on the Ras–mitogen-activated protein kinase (MAPK) signaling pathway[103]. In rabbit proximal renal tubular cells, we demon-strated that the growth-promoting effects of HGF in-volve the activation of Src, whereas the HGF-inducedtubulogenic differentiation (for example, formation oflong microvilli at the apical cell membrane) was notFig. 2. Morphogenic effects of HGF on cultured proximal tubular cells.

The differentiated rabbit proximal tubular cell line PT-1 was cultured influenced by src-interfering tyrosine kinase inhibitorsin Dulbecco’s modified Eagle’s medium (DMEM) as described [94, 95]. [95]. Invasive cell growth upon stimulation of c-met re-Cells were incubated for 48 hours in serum-free medium alone (A; bar 5

quires the concomitant activation of Ras and PI-3 kinase10 mm) or in the presence of HGF (1029 mol/L; B). HGF induced cellscattering (thin arrows) and tubulogenesis (thick arrows). Reprinted [49] or Src and PI3 kinase [104]. Scattering needs PI3-with permission from Jehle et al [94]. kinase activation [105–107] and in some cell types also

requires an additional effector [108]. Morphologicalchanges induced by HGF in MDCK cells are related tomodifications in cell polarity with alteration of synthesisthe first stages of kidney tubulogenesis, other growth fac-rate and interaction between b-catenin and E-cadherintors may replace the morphogenetic role of HGF. c-met[109]. The cell spreading response in this model is depen-knockout kidney cells form tubules in vitro upon stimula-dent on the activation of the small guanine 59-triphos-tion with TGF-a [89]. Another study showed that TGF-aphate (GTP)-binding proteins Ras and Rac. PI3 kinaseand EGF induce tubulogenesis of murine inner medul-is also involved in mediating the effects of HGF on tubu-lary collecting duct cells [90]. Coculture experiments re-logenesis [110]. In MDCK cells, HGF-induced tubulo-vealed that HGF produced by mesangial cells stimulatesgenesis and branching are enhanced by several compo-endothelial cell growth and that this interaction is nega-nents of the cell matrix, such as laminin, fibronectin, andtively modulated by TGF-b and angiotensin II [73].entactin, but are inhibited by type IV collagen, heparanThese authors suggested that negative regulation of localsulfate proteoglycan, vitronectin, and TGF-b [111]. InHGF production by both factors may play an importantthese cells, the branching development is regulated byrole in the pathogenesis of renal disease.phosphorylation processes mediated by protein kinase AThe morphogenetic and motogenic effects of HGF(PKA), protein kinase C (PKC), and Ca21/calmodulin-were first described in the MDCK cell line [91] and weredependent kinases [111]. Another protein involved inconfirmed in a variety of other epithelial cells [92–94].the scattering and tubulogenesis mediated by HGF inIn differentiated rabbit proximal tubular cells, HGF ex-kidney cells is the membrane-cytoskeleton linker ezrin,hibits potent mitogenic, morphogenetic, motogenic, andwhich is phosphorylated by c-met [112]. Downstream ofepithelial cell-differentiating effects under serum-freeGrb2 [106], the tubulogenic HGF response is dependentconditions [95]. Among its pleiotropic effects, the induc-

tion of cell scattering plays a pivotal role (Fig. 2). Scatter- on the STAT pathway [113].

Vargas et al: HGF in renal failure1430

nephrectomy or partial hepatectomy [118]. An increaseof HGF and its mRNA was also detected in rats afterunilateral nephrectomy and CCl4 treatment, with con-comitant internalization of c-met [119], and a transientincrease of HGF precedes the regenerating events in ratkidney after vitamin E depletion combined with glutathi-one depletion [120]. HGF and HGF mRNA increase inrat kidney after ischemia or HgCl2-induced nephrotoxic-ity and levels remain augmented during the phase oftubular regeneration [121]. On the other hand, the renalexpression of c-met increases in rats after ischemia, uni-lateral nephrectomy, or folic acid treatment [122]. A linkbetween renal hypertrophy observed in diabetic rats was

Fig. 3. Stimulation of c-met gene expression by cytokines and growth also proposed in relationship with the elevation of c-metfactors in cultured renal epithelial cells. Mouse inner medullary collect-in medullar and cortical tubular epithelium [123]. Aing duct epithelial cells (mIMCD-3) were incubated for 24 hours in

serum-free medium without (control) or with specific cytokines or spontaneous mouse model of chronic renal disease [im-growth factors at a concentration of 10 ng/mL. The total cellular RNA mune complex glomerulonephritis (ICGN) strain devel-was isolated and hybridized using rat c-met cDNA as a probe. The

oping glomerular sclerotic injury, tubular atrophy, andsame blot was stripped and reprobed with GAPDH to confirm equalloading of the RNA. Similar results were obtained using proximal renal dysfunction until 17 weeks of age] was used totubule-derived opossum kidney epithelial cells. Reprinted with permis- investigate whether HGF may inhibit the progression ofsion from Liu et al [116].

tubulointerstitial fibrosis [124]. When recombinant HGFwas injected into these mice during a four-week period(from weeks 14 through 17 after birth), DNA synthesisof tubular epithelial cells was found to be 4.4-fold higher

Evidence that HGF may represent an important reno- than in mice without HGF injection, thereby suggestingtropic growth factor came from cell culture studies, ani- tubular parenchymal expansion promoted by HGF. No-mal experiments, and findings in human kidney disease. tably, HGF suppressed the expression of TGF-b and ofHGF promotes DNA synthesis of several renal cell types, PDGF as well as myofibroblast formation in the affectedincluding tubular and glomerular epithelial cells [94, 114, kidney. Consequently, HGF completely inhibited the on-115]. The mitogenic effects of HGF on renal tubular set of tubulointerstitial fibrosis and attenuated the pro-epithelial cells are regulated by cell–cell interactions [114]. gression of glomerulosclerosis, both preventing manifesta-DNA synthesis stimulated by HGF was high at a low cell tion of renal dysfunction. From these results, supplementdensity and was strongly suppressed at a higher one. These therapy with HGF may be taken into consideration as aresults suggest that HGF may act not only as an inductor, novel option for prevention and treatment of chronicbut also as a modulator in renal regeneration and com- renal disease.pensatory renal growth. In conditions of renal injury medi- Increased HGF mRNA transcripts were detected inated by folic acid treatment, HGF up-regulates c-met in mesenchymal and tubular epithelial cells of rejecting kid-a tissue-specific manner, acting primarily at the transcrip- ney [125], and elevated serum HGF levels were sug-tional level by stimulating the c-met promoter activity [116]. gested to indicate renal rejection [126]. Serum HGF lev-This study also demonstrated up-regulation of c-met ex- els correlate with serum creatinine in chronic renalpression in renal epithelial cells in vitro by interleukins, failure patients, indicating a response to the organ dam-TGF-b, EGF, insulin-like growth factors (IGFs), and age or decreased clearance by the insufficient kidney.platelet-derived growth factor (PDGF) (Fig. 3). Because In acute renal failure, elevated urine HGF levels aretissue regeneration results from the integration of the described as consistent with a role for HGF in promotingcomplex interplay among many different growth factors, tubule cell proliferation [127], whereas patients withc-met seems to be at a convergence point and may play chronic glomerular or polycystic disease, as well as pa-a key role in the processes leading to the completion of tients with advanced chronic renal insufficiency andthe entire regenerative course. In the adult mouse kid- healthy controls, show detectable but low urine HGFney, in situ hybridization experiments localized c-met in levels [127, 128]. Hemodialysis with cellulosic or biocom-proximal and distal tubules [63]. During experimental patible membranes and with or without heparin stimu-acute renal failure, elevated HGF mRNA levels were lates the increase of HGF levels in circulation, and serumfound in kidney and liver, but c-met mRNA was up- of dialysis patients induces the HGF production in mono-regulated selectively at the site of greatest tubular injury nuclear cells and fibroblasts [129]. HGF was also detectedor hypertrophy [117]. HGF mRNA and peptide levels in cyst fluids in cases of renal cystic disease, suggesting

a possible causal coherence with this pathology [130]. Fur-increases in kidney and spleen in response to unilateral

Vargas et al: HGF in renal failure 1431

sion. In hepatic nonparenchymal cell lines, HGF trans-fection produces a loss of cell contact inhibition and thegeneration of large, invasive tumors in nude mice [134].Hepatocyte cell lines expressing HGF display the samecharacteristics [133]. In fibroblasts, simultaneous expres-sion of HGF and c-met is required for tumorigenesis[135]. Bladder carcinoma cells exhibit a scattered pheno-type when transfected with HGF and are more invasivethan untransfected cells [136]. In renal carcinogenesis,c-met plays a role as an inductor of invasiveness. In 87%of renal carcinomas and in one renal carcinoma cell line,c-met was detected [137]. In SMTK-R3, another renalcarcinoma cell line, HGF stimulates not only cell motilityand proliferation, but also the glycolipid sulfotransfer-ases activity, indicating multiple biological effects in re-nal cell carcinomas [138]. In this context, several reportssuggested a relationship between the human hereditarypapillary renal carcinoma and mutations in the tyrosinekinase domain of c-met [100]. In contrast, both HGFand c-met mRNA levels are normal in nephroblastomas[139]. Abnormal overexpression of HGF produces mes-enchymal and epithelial tumors in mice with c-met acti-vation by an autocrine loop [140].

The role of HGF/c-met in tumor progression may beexplained in part by an association of the multifunctionaldocking site of c-met (Fig. 1B) with the anti-apoptoticprotein BAG-1 and other substrates [141, 142]. In oralsquamous carcinoma cell lines, HGF acts as a promoterof cell migration and invasion with tyrosine phosphoryla-Fig. 4. Endothelin-1 release by cultured proximal tubular (PT-1) cells,

coincubated with cyclosporine A and hepatocyte growth factor (HGF, tion of p125FAK kinase [143]. In contrast to these data,1028 mol/L) or epidermal growth factor (EGF, 1028 mol/L). Data are the antiproliferative effects of HGF were described inmeans 6 SEM, N 5 6. ***P , 0.001 vs. cyclosporine 50 mg/L; 111P ,

melanoma, squamous carcinoma, and hepatocellular car-0.001 vs. cyclosporine 500 mg/L. Reprinted with permission from Hauget al [132]. cinoma cell (HCC) lines [144]. The introduction of an

HGF vector in HCCs inhibits cell growth in vitro anddiminishes tumor growth in vivo, but stimulates growthof normal hepatocytes [145]. Growth inhibition and in-duction of apoptosis by HGF have been shown also inthermore, HGF may be involved in the pathogenesis oftransformed rat liver epithelial cells [146].inflammatory renal diseases. Rat mesangial cells coexpress

HGF and c-met in response to IL-6 stimulation in vitro[131]. In cultured renal proximal tubular cells, we showed DIAGNOSTIC AND THERAPEUTICthat HGF potently inhibits the cyclosporine A- or tacroli- IMPLICATIONS OF HGF/c-met INmus-induced endothelin-1 release (Fig. 4) [132]. Taken KIDNEY DISEASEStogether, the above-mentioned studies indicate that HGF,

A plethora of clinical applications for treatment withdespite its activity on promoting renal regeneration inHGF or HGF analogue peptides might be raised in theacute processes, may also be involved in the developmentnear future [147]. Clinical indications for HGF treatmentof histologic changes associated with the loss of kidneywere suggested in kidney, liver, and lung regeneration,functionality in chronic diseases.as well as in the treatment of diabetes mellitus, gastriculcers, and vascular or neuroneal diseases [147]. A recent

HEPATOCYTE GROWTH FACTOR, c-met, AND report describes the reversion of liver cirrhosis in ratsTUMOR CELL GROWTH injected with an HGF expression vector [148]. Reports

connect the severity of arterial hypertension with signifi-Hepatocyte growth factor and c-met are involved incantly increased circulating HGF levels, probably as amalignant cell growth. HGF transforms immortalizedconsequence of endothelial cell damage [149]. A markedmouse epithelial cells [133], and several lines of evidence

suggest that its scatter ability is critical in tumor progres- elevation of HGF serum levels could also be found in

Vargas et al: HGF in renal failure1432

the first stages of myocardial infarction but not in other thesis in tubular epithelial cells, attenuates glomerulo-sclerosis, and inhibits almost totally the development ofheart diseases [150]. Thus, HGF may be used as a serum

marker to monitor the course of myocardium infarction tubulointerstitial fibrosis [124]. In contrast, transgenicmice expressing HGF under control of the metallothio-and hypertension-induced endothelial dysfunction. In di-

verse neoplastic diseases, HGF and/or c-met were also nein promoter develop glomerulosclerosis, tubular hy-perplasia, and polycystic kidney disease [154]. The sameproposed as novel clinical markers of diagnostic or prog-

nostic value. Probably the most exciting possibilities of animals show also a marked incidence of tumors of di-verse origin [140], probably because of the systemic over-the clinical utilization of HGF and/or c-met are related

to therapy with two basic variants: HGF or c-met block- expression of HGF. In fact, in the less affected metallo-thionein-HGF mice line, the severity of kidney diseaseade in proliferative diseases or HGF-induced tissue re-

generation [147]. Protocols including the preadministra- is not correlated to the HGF level in serum, but to theliver weight. These findings were interpreted as a contri-tion of HGF to prevent nephrotoxic side effects of drugs

or to induce restoration of functional integrity in diverse bution of the liver hypertrophy and the systemic HGFtissues after surgical manipulation may be of clinical levels to the onset of kidney disease in these animals.relevance. Finally, our comprehension of the factors involved in

Several experimental models indicate a possible thera- the subtle equilibrium between HGF-induced cell andpeutic application of HGF in kidney diseases. In animal organ regeneration and tumorigenesis is still incomplete,models, HGF is at least as potent as EGF or IGF-1 to and several problems have to be solved before consider-recover the renal function after acute injury [121, 151]. ing HGF as a therapeutical agent in human kidney dis-The administration of HGF accelerates recovery from ease. The short half-life and fast clearance of HGF fromacute ischemic renal injury in rats by enhancing regener- circulation may be overcome by HGF variants with aation of proximal tubular epithelium [152]. In this study, longer life in circulation [61]. However, the use of suchthe beneficial effects of HGF on the clinical outcome agents may be limited by enhanced systemic side-effects.are indicated by significantly lower creatinine and blood A therapeutical challenge for the future could be theurea nitrogen levels, enhanced insulin clearances, re- design of tissue-specific vectors to express HGF in dam-duced mortality, and much less injury in kidney histolog- aged organs, most importantly in kidney during acuteies. Furthermore, the administration of HGF may even renal failure. This could be an approach to avoid theprevent acute renal failure when given in a prophylactic deleterious consequences of systemic HGF expressionmanner [121]. HGF not only activates tubular repair [140] and to use the amazing biological potency of thisprocesses but also ameliorates the initial injury (for ex- renotropic growth factor.ample, cisplatin toxicity) by protecting renal epithelialcells from undergoing apoptosis [72]. It is important, ACKNOWLEDGMENTShowever, to discuss the renoprotective action of adminis-

This work was supported by the Landesforschungsschwerpunkt Ba-tered HGF on the basis of endogenous HGF expression, den-Wurttemberg: Modulation von Wachstumsfaktoren als Therapie-

prinzip (P.M.J.). We thank PD Dr. Cornelia Haug for providing Figure 4.which changes in acute renal failure. When this conditionwas induced in rats by ischemia or by HgCl2 administra-

Reprint requests to PD Dr. Peter M. Jehle, University of Ulm, Internaltion, DNA synthesis occurred predominantly in the renal Medicine II, Division of Nephrology, Robert-Koch-Straße 8, 89081 Ulm,tubular cells located in the outer medulla, with a peak Germany.

E-mail: peter.jehle@medizin.uni-ulm.deat 48 hours after the treatments [153]. In both renalinjuries, mRNA levels and activity of HGF in the kidney

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