Abstract. An understanding of the mechanisms underlying the
formationof renal lesions is necessary for the development of strategies
aimingto delay the progression of chronic renal failure. The generationof
transgenic mice in the past 20 years has contributed significantlyto the
study of this phenomenon. Overexpression and/or inactivationof single factors
in renal tissue demonstrated that moleculessuch as growth factors,
proto-oncogenes, and renin-angiotensinsystem elements play major roles in
renal deterioration. Severalmouse models of renal injury have been developed
in the past10 yr. Transgenic mice that exhibit a normal phenotype under
physiologicconditions allow analysis of the roles of single factors inthe
progression of chronic renal failure when renal injury modelsare used. Using
this strategy, it was demonstrated that vascularadaptation, which is a
process that involves the endothelin/nitricoxide balance, is essential for
the survival of mice after nephronreduction and that the epidermal growth
factor/activator protein-1/Bcl-2pathway is involved in the development of
renal lesions afterrenal injury, possibly via adjustment of the
proliferation/apoptosisbalance. Moreover, it was demonstrated that selective
inhibitionof epidermal growth factor signaling in the kidney successfully
preventsthe progression of chronic renal failure. These results indicatethe
power of transgenesis for elucidation of the pathogenesisof renal
disease.
The relentless progression of human renal disease to end-stagerenal
failure is a phenomenon that remains largely unexplained.Recently, two
approaches have given new impetus to the studyof progression. The first is
the development of several mousemodels of renal injury that mimic human renal
disease. The secondis the generation of several lines of transgenic mice that
lackor overexpress factors thought to be involved in renal deterioration.We
combined these two approaches to investigate the differentsteps in the
cascade of events leading to renal destructionafter renal injury.
Role of the Genetic Background in Experimental Models of Chronic
Renal Injury in Mice
In the past century, several models of chronic renal injuryhave been
developed in rats for analysis of the consequencesof chronic renal failure,
such as metabolic disorders, hypertension,and renal deterioration. The
reduction of renal mass is themost widely used model to investigate the
molecular mechanismsunderlying the progression of chronic renal failure
(1). Indeed,numerous studies
have demonstrated that severe nephron lossinduces renal deterioration
independent of the initial process(ischemic, toxic, or immunologic). Two
models of nephron reductionare currently used, i.e., unilateral
nephrectomy and subtotalnephrectomy. Unilateral nephrectomy has been used
mainly tostudy renal compensatory growth and to accelerate the progressionof
renal lesions in other models of renal injury, such as toxicagent-induced
nephropathy, diabetes, or deoxycorticosteroneacetate (DOCA)-salt hypertension
(1). Unilateral nephrectomy
aloneinduces very few lesions in animals (rats and mice), exceptin old ones.
Subtotal nephrectomy is performed using two mainprocedures, i.e.,
ligation of the branches of the renal arteryor ablation of the two poles of
the left kidney, followed bycontralateral nephrectomy. The first method
causes severe andimmediate hypertension because of renal ischemia; the second
isless hypertensive and allows more accurate quantification ofthe degree of
renal ablation. Whichever method is used, subtotalnephrectomy in rats induces
(1) immediate and sustained vasodilation,which is paralleled by an
increase in GFR in the remaining nephrons;(2) compensatory growth of
the remnant kidney, which is observedbetween the first and second week after
surgery; and (3) renallesions (glomerulosclerosis, tubular atrophy
and/or dilation,and interstitial fibrosis), which develop approximately 1 mo
aftersurgery and lead to complete destruction of the remnant kidney.In rats,
the evolution toward end-stage renal failure dependsmainly on the severity of
the initial renal ablation and maybe modified by environmental factors, such
as diet or drugs(1). To date,
very few data on the natural history of renalmass reduction in mice are
available. It is clear that, in miceas well, hemodynamic adaptation occurs
and plays a major rolein maintaining renal function, as discussed below. The
kineticsand magnitude of renal compensatory growth are apparently similarin
mice and rats. We observed that, 14 d after 3/4 nephrectomy,the weight of the
remnant kidney doubled in rats and mice andbecame close to that of control
animals (2) (unpublished
observations).However, the development of renal lesions is not constant in
miceand depends on the genetic background. Indeed, in C57BL6xDAB2mice,
75% reduction of the total renal mass induced only moderatetubular lesions
even 8 mo after surgery. In contrast, in FVBmice, similar nephron reduction
resulted in severe glomerulosclerosisand tubular cystic dilations as early as
2 mo after surgery(unpublished observations). Along the same line, unilateral
nephrectomyinduced glomerulosclerosis in ragged oligosyndactyly pintailmice
but not C57BL6 mice (3), a
strain that is resistant tothe development of renal lesions up to 44 wk after
subtotalnephrectomy (4). In
contrast, subtotal nephrectomy induced severeglomerulosclerosis in 129/sv
mice 4 mo after surgery (5).
Takentogether, these results emphasize the key role played by geneticfactors
in the response to nephron reduction and suggest a roleof
"modifier" genes in the evolution of renal diseases.
To use lines of C57BL6xDAB2 transgenic mice, we developed threeother
experimental models of chronic renal injury, i.e., (1)
prolongedrenal ischemia (50-min clamping of the renal vascular pedicle),
(2)folic acid-induced nephropathy (a single intraperitoneal
injectionof folic acid), and (3) cisplatin-induced nephropathy (a
singlesubcutaneous injection of cisplatin). In C57BL6xDAB2 mice, all
threeprocedures induced intense tubular cell proliferation, followedby the
development of numerous areas of atrophic tubules, markedinterstitial
fibrosis, and mild multifocal mononuclear cellinfiltrates. These lesions were
less severe in folic acid-treatedanimals. It is noteworthy that the same
procedures did not resultin chronic renal lesions in rats, again
demonstrating the difficultyof adapting the well known rat models of renal
injury to mice.However, mice, like rats, are susceptible to the development
ofmoderate glomerular lesions after anti-Thy antibody injectionand severe
renal atrophy after ureteral obstruction.
Two Different Strategies to Analyze Renal Deterioration Using
Transgenic Mice
Several hypotheses have been proposed to explain the developmentof renal
lesions after nephron reduction, i.e., glomerular hyperfiltration,
glomerularhypertension, tubular hypermetabolism, and renal hypertrophy
(6).All hypotheses rely
primarily on differences observed betweenprotective and non-protective
conditions, particularly the changesinduced by protein or sodium diets and by
antihypertensive drugs.The complexity of the pathways modified by these
treatmentsmade it difficult to reach conclusions regarding the roles of
singlefactors. Indeed, an ideal model to study the direct effect ofa
candidate factor on the development of renal lesions requiresthat the kidney
be continuously and selectivity exposed to ordeprived of that single factor.
This goal could be achievedby inactivation of the gene encoding a specific
factor or introductionof a gene into renal tissue, via germline gene
manipulationor in vivo gene transfer
(7,8).
Selective renal overexpressioncan be obtained by using promoters that target
transgene expressionto different segments of the nephron
(7). Similarly, the useof
these promoters in the Cre/lox system could allow targetgene
inactivation in the kidney. To date, hundreds of differenttransgenic mouse
lines have been generated, and a number spontaneouslyexhibit a renal
phenotype (9). Several mouse
lines have beenproduced to investigate the roles of growth factors
(9,10),
thefibrinolytic system (11),
and the angiotensin II pathway
(12)in renal deterioration.
These models provided clear evidencethat several of these molecules are
involved in the developmentof renal lesions. However, their role in the study
of chronicrenal failure is limited by the fact that these mice spontaneously
developedrenal lesions, in the absence of an exogenous injury. This ledto
increased interest in the use of transgenic mice, which reproducewithout an
obvious phenotype under physiologic conditions, toanalyze the effects of
renal injury. In our laboratory, we chosethis strategy to investigate the
role of vascular adaptationsand renal growth in the development of renal
lesions.
Study of Hemodynamic Adaptation to Nephron Reduction Using
Vimentin-Null Mice
Reduction of renal mass is known to induce immediate and sustained
vasodilation,which is paralleled by increases in GFR in remaining glomeruli.
Severalstudies suggested that these hemodynamic adaptations participatein
the development of renal lesions by stretching mesangialcells, changing the
capillary permeability, and damaging thesurrounding endothelial and
epithelial cells (6).
Vimentin is a class III intermediate filament protein that ismainly
expressed in mesenchyme-derived cells, including endothelialand vascular
smooth muscle cells (13). In
normal adult kidney,vimentin is strongly expressed in both vessels and
glomeruli.The observation that the vimentin network is modified by mechanical
stressin vitro (14)
suggests that this protein is involved in theregulation of vascular tone,
including vascular adaptation tonephron reduction. A line of mice bearing a
null mutation ofvimentin gene has been generated
(15). Interestingly, these
animalsdevelop and reproduce without an obvious phenotype. Moreover,they
exhibit normal renal morphologic features and functionsunder physiologic
conditions (16). Therefore, we
used homozygousvimentin-null mice (Vim-/-) and wild-type
littermates (Vim+/+)to investigate the role of vascular
adaptation to nephron loss
(17).Ablation of 75% of the
total renal mass was lethal, within 3d, for 100% of
Vim-/- mice, whereas no lethality was observedamong their
Vim+/+ littermates. Death in Vim-/-
mice resultedfrom end-stage renal failure. In fact, plasma creatinine
concentrationswere higher in Vim-/- animals than in
Vim+/+ littermates andwere comparable to values observed
for wild-type binephrectomizedmice. Because the morphologic features of
Vim-/- remnant kidneyswere normal, we hypothesized that
renal failure in Vim-/- miceresulted from increased
arterial vasoconstriction and/or reducedarterial vasodilation. To test this
hypothesis, we analyzedthe ability of renal resistance arteries from mutant
and wild-typemice to respond to chemical and mechanical stimuli in
vitro.In renal arteries from Vim-/- mice, the
contractile responseto endothelin (ET) was selectively increased, whereas
sensitivityto acetylcholine, a nitric oxide (NO)-dependent relaxing agent,
wasreduced. With respect to the responses to mechanical stimuli,the myogenic
tone (stretch stress) was increased in Vim-/- renal
arteries,whereas flow-induced dilation (shear stress), which dependson
endothelial NO synthesis, was decreased. Similarly, remnantkidneys from
Vim-/- mice synthesized more ET but less NO, comparedwith
kidneys from wild-type animals. Finally, infusion of bosentan(an ET-1
receptor antagonist) prevented death in 100% of Vim-/-
nephrectomizedmice and restored renal function to a range similar to that
observedfor wild-type littermates. Taken together, these results illustrate
theextent to which the ET/NO ratio is crucial in the maintenanceof renal
function after nephron reduction.
The molecular mechanisms responsible for vascular dysfunctionin mice
lacking vimentin remain unclear. Cytoskeletal proteinsare thought to
participate in the mechanotransduction of shearstress by modulating the
transcription of several molecules,including ET and NO synthase
(18). It was recently
suggestedthat nephron reduction induced flow-induced dilation of renal
arteries.We propose that, in mutant mice, the lack of a vimentin network
impairednephrectomy-induced shearstress transmission, giving rise tothe
ET/NO imbalance.
The fact that Vim-/- mice die within 72 h after surgery
precludesconclusions regarding the role of hemodynamic adaptation inthe
renal deterioration process. However, our results providethe first evidence
that these processes are necessary for survivalafter renal mass reduction,
and they support the careful useof drugs aiming to reduce vascular
modifications, at least inthe early period after nephron loss.
Role of the Epidermal Growth Factor Pathway in Renal Growth and Renal
Deterioration
Reduction of renal mass triggers molecular and cellular eventsthat promote
compensatory growth of the remaining nephrons,which precedes glomerular and
tubular lesions and ultimatelyleads to end-stage renal failure
(6). The mechanisms that link
compensatoryrenal growth to renal deterioration remain poorly understood.The
occurrence of both glomerular enlargement and cystic tubulardilation, as well
as expansion of the interstitial space, suggeststhat excessive cell
proliferation and/or defective cell deathplays a key role. Both proliferation
and apoptosis of renalcells could be triggered by a number of growth factors
and/orproto-oncogenes that are synthesized within the kidney and actthrough
specific membrane-bound receptors, possibly throughautocrine or paracrine
pathways (10). The expression
of thesemolecules in the kidney is increased in experimental and human
nephropathies(10). Among
these paracrine modulators, epidermal growth factor(EGF) is of special
interest because (1) its expression is increasedin several renal
pathologic conditions characterized by intensecell proliferation, such as
nephron reduction (19),
polycystickidney disease
(20), and adenocarcinoma
(21); (2) transgenic
micethat overexpress different molecules of the EGF pathway developrenal
lesions
(22,23,24);
and (3) experimental approaches aimingto block EGF receptor (EGFR)
signaling halt the evolution ofrenal disease in polycystic kidneys
(25) and adenocarcinomas
(26).Moreover, we
demonstrated that the entire EGFR/EGF/activatorprotein-1 (AP-1) pathway is
overexpressed after nephron reductionin rats
(10) and this upregulation is
blunted by moderate restrictionof dietary sodium, which reduces the
progression of renal lesions
(27,28).
Theseresults suggest that EGFR activation could be a major determinantin the
development of renal lesions, possibly via adjustmentof the
proliferation/apoptosis balance. To test this hypothesis,we used three
different lines of transgenic mice, i.e., dominant-negativeEGFR
mice, Bcl-2 mice, and junD-null mice.
Study of the EGF Pathway in Renal Deterioration Using
Dominant-Negative EGFR Mice
Genetic approaches aiming to block EGFR signaling face two major
difficulties,namely that EGFR-null mice are not postnatally viable and that
inactivationof one of the numerous EGFR ligands might not be informative
becauseof ligand redundancy. Therefore, we used a dominant-negativestrategy
to generate transgenic mice expressing a carboxyl-terminallytruncated EGFR
under the control of the kidney-specific typeI -glutamyl
transpeptidase promoter (29).
As expected, the transgenewas expressed exclusively in basolateral membranes
of proximaltubular cells. Under physiologic conditions, mice exhibitednormal
renal morphologic features and functions. The mutantreceptor behaved as a
dominant-negative effector because itprevented EGF-signaled EGFR
autophosphorylation after EGF infusion.Transgene expression did not affect
kidney development, probablybecause of the weak expression of the
-glutamyl transpeptidasepromoter during development. In addition,
phosphorylation ofthe endogenous receptor was not completely prevented by
thisdominant-negative strategy. It is noteworthy that kidneys alsodeveloped
normally in waved-2 mutant mice, in which the mutatedEGFR is only
partially impaired (30).
We next investigated the effect of inhibition of the EGF pathwayon the
development of renal lesions in two models of renal injury,i.e.,
subtotal nephrectomy and prolonged renal ischemia. Eightmonths after 75%
ablation of the total renal mass, tubular lesionswere less severe in
transgenic mice than in wild-type littermates.This effect was associated with
a reduction of tubular cellproliferation, suggesting that activation of EGFR
is one ofthe first events triggering cell proliferation after nephron
reduction.A similar mechanism was recently implicated in the developmentof
tubular dilation in several models of polycystic kidney disease
(31).Twenty-eight days after
prolonged ischemia (50-min clampingof the left renal vascular pedicle),
tubular atrophy and interstitialfibrosis were reduced in transgenic mice,
compared with wild-typelittermates. The beneficial effects of the transgene
includedreductions in tubular cell proliferation, interstitial collagen
accumulation,and mononuclear cell infiltration. Involvement of the EGF
pathwayin fibrogenic processes was previously observed in lung, usinga
transgenic approach. Indeed, mice that selectively overexpressedtransforming
growth factor-, a ligand of EGFR, in lung developedseveral areas of
fibrotic lesions (32). These
lesions were reversedin double-transgenic mice that expressed both
transforming growthfactor- and a dominant-negative mutated EGFR
(33). The mechanismby which
tubular EGF induces interstitial fibrosis in kidneyremains to be elucidated.
From in vitro results, we speculatethat, in proximal tubules, EGF
could stimulate (1) the conversionfrom tubular cells to fibroblasts,
via increases in fibroblast-specificprotein-1 expression
(34), (2) the
synthesis of matrix collagens
(35),and (3) the
production of tubular cytokines, which mediate thecross-talk between tubular
and interstitial cells
(36).
Study of Proliferation/Apoptosis in Renal Deterioration Using Bcl-2
and junD-Null Mice
Apoptosis (programmed cell death) is now recognized to playan important
role in the regulation of the number of renal cellsin both acute and chronic
renal failure (37). Bcl-2, a
potentinhibitor of cell death, is suspected to play a pivotal rolein these
processes (38). In proximal
tubular cells, EGF stimulatescell proliferation via AP-1 activation and
inhibits apoptosisvia Bcl-2. The respective roles of cell proliferation and
celldeath in renal deterioration were investigated by using Bcl-2
(39)and junD-null
mice (40). Both strains
exhibit an apparentlynormal renal phenotype under physiologic conditions.
We demonstrated that, after prolonged renal ischemia, mice that
overexpressedBcl-2 in proximal tubular cells developed more severe tubular
atrophy,interstitial fibrosis, and mononuclear cell infiltration thandid
wild-types littermates (F. Terzi, A. Winckel, unpublishedobservations). This
impairment was associated with a decreasein apoptosis but also with an
increase in cell proliferationin proximal tubules. The stimulation of cell
proliferation seemsto be specific to renal tubular cells, because
overexpressionof Bcl-2 inhibits cell proliferation by blocking cell cycle
entryin lymphocytes and thymocytes
(41). Elucidation of the
reasonfor this discrepancy requires further investigation.
AP-1 is a transcription factor that results from heterodimerizationof one
of the four Fos proteins (c-Fos, FosB, Fral, and Fra2)with one of the three
Jun partners (c-Jun, JunB, and JunD)
(42).AP-1 activation mediates
the mitogenic effects of polypeptidegrowth factors, including EGF. In
previous works
(2,28),
wedemonstrated that the expression of c-Fos and c-Jun proteins,the two major
partners in the AP-1 complex, is increased afternephron reduction. Because
JunD protein, in contrast to c-Jun,negatively regulates cell growth
(43), we evaluated the effect
ofnephron reduction in mice lacking the junD gene
(40). Two monthsafter 75%
nephron reduction, junD-null mice developed severeglomerulosclerosis
and tubular dilations, whereas no lesionswere observed in wild-type
littermates (F. Terzi, M. Burtin,unpublished observations). The more severe
renal lesions wereassociated with increased cell proliferation, confirming
thecrucial role of AP-1 activation in these phenomena.
In conclusion, using several transgenic approaches, we demonstratedthat
the activation of the EGF/AP-1/Bcl-2 pathway is a majordeterminant in the
development of renal lesions after renalinjury, possibly via adjustment of
the proliferation/apoptosisbalance. Moreover, we demonstrated that selective
inhibitionof EGF signaling in the kidney successfully prevents the
progressionof chronic renal failure. A specific inhibitor of EGFR tyrosine
kinaseactivity was recently produced. Its use halts the evolutionof
polycystic kidney disease in mice
(44). Taken together, these
findingsstrongly suggest that strategies aiming to block the EGFR pathway
couldbe useful in delaying the progression of chronic renal failurein human
patients.
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Top
Abstract
Introduction
-glutamyl
transpeptidase promoter (29).
As expected, the transgene was expressed exclusively in basolateral membranes
of proximal tubular cells. Under physiologic conditions, mice exhibited normal
renal morphologic features and functions. The mutant receptor behaved as a
dominant-negative effector because it prevented EGF-signaled EGFR
autophosphorylation after EGF infusion. Transgene expression did not affect
kidney development, probably because of the weak expression of the
, a ligand of EGFR, in lung developed several areas of
fibrotic lesions (32). These
lesions were reversed in double-transgenic mice that expressed both
transforming growth factor-
1-independent
mechanism. Kidney Int 52:637
-647, 1997[Medline]
