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Am J Physiol Renal Physiol 289:227-234, 2005. doi:10.1152/ajprenal.00453.2004

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Am J Physiol Renal Physiol 289: F227–F234, 2005;
doi:10.1152/ajprenal.00453.2004. Invited Review

Insights into the mechanisms of renal fibrosis: is it possible

to achieve regression?
Christos Chatziantoniou and Jean-Claude Dussaule
Institut National de la Santé et de la Recherche Médicale Unité 702, Hôpital Tenon,
and AP-HP, Laboratoire de Physiologie, Faculté de Médecine St. Antoine, Paris, France

Chatziantoniou, Christos, and Jean-Claude Dussaule. Insights into the mech-

anisms of renal fibrosis: is it possible to achieve regression?. Am J Physiol Renal
Physiol 289: F227–F234, 2005; doi:10.1152/ajprenal.00453.2004.—Recent evi-
dence suggests that the progression of renal fibrosis is a reversible process, at least
in experimental models. The present review summarizes the new insights concern-
ing the mechanisms of progression and regression of renal disease and examines
this novel evidence under the light of feasibility and transfer to human nephropa-
thies. The involved mechanisms are discussed with particular emphasis on the
fibrotic role of vasoactive peptides such as angiotensin II and endothelin and
growth factors such as transforming growth factor (TGF)-␤. The possibility of

Downloaded from ajprenal.physiology.org on August 4, 2010

regression is introduced by presenting the in vivo efficiency of antihypertensive
treatments and of systems that antagonize the fibrogenic action of TGF-␤ such as
bone morphogenic protein-7 and HGF. Finally, we provide a brief description of
the promising future directions and clinical considerations about the applications of
the experimental data to humans.
chronic renal failure; collagen; angiotensin; growth factors; metalloproteinases

RENAL FIBROSIS IS DEFINED by the abnormal accumulation of
extracellular matrix that replaces normal kidney structures.
Contrary to the kidney, regression of fibrosis is well estab-
lished in other tissues, such as heart, liver, and skin (19, 20,
23). Because renal fibrosis appears irrespective of the under-
lying disease (hypertension, diabetes, infection, inflammation
of renal blood vessels and glomeruli, kidney stones, and cysts)
and originating renal compartment (renal vessels, glomeruli,
tubules), it is generally believed that is under the control of a
common final physiopathological pathway independent of the
primary cause. Thus identifying and targeting the systems
participating in this pathway may lead to efficient treatments
against renal fibrosis and failure regardless of the initiating
pathology. Over the last few years, studies in humans gave
hope by showing that antihypertensive treatments can indeed
induce relative renoprotection. After an initial observation that
blockade of the angiotensin II action protects against the
progression of renal insufficiency in patients with various renal
diseases (such as glomerulopathies, interstitial nephritis, ne-
phrosclerosis, polycystic kidney disease, or diabetic nephrop-
athy) (54), large-scale studies concerning hypertensive patients
with type 2 diabetes demonstrated the renoprotective efficiency
of angiotensin II antagonism (13, 51, 60). In these studies,
angiotensin II receptor antagonism reduced microalbuminuria
and slowed the rate of decline of the filtration rate; these
renoprotective effects were independent of the blood pressure
decrease, supporting the notion of dissociation between sys-
temic and local actions of angiotensin II in kidneys. Despite
these promising results, the challenge remains to go beyond
Address for reprint requests and other correspondence: C. Chatziantoniou,
INSERM U702, 4 Rue de la Chine, Hôpital Tenon, 75020 Paris, France
(e-mail: christos.chatziantoniou@tnn.ap-hop-paris.fr).
http://www.ajprenal.org 0363-6127/05 $8.00 Copyright © 2005 the American Physiological Society
slowing down the progression and to try to achieve regression
of renal fibrosis and restoration of renal structure. The forma-
tion of extracellular matrix follows schematically three distinct
steps: synthesis of the mature protein (a complex process
starting at synthesis of propeptides, followed by cleavage and
assembly of the peptidic chains to form the mature protein);
extracellular stabilization with the aid of matrix “receptors”
and cross-linking enzymes; and catabolism by specific protein-
ases. Fibrosis is developed when the rate of synthesis and
stabilization of matrix is exaggerated and/or when the capacity
of degradation is decreased. In this review, we will present data
obtained mainly in experimental rodent models that provided
novel insights into the cellular mechanisms participating in the
progression and identified possible targets to achieve regres-
sion of renal fibrosis.
INHIBITION OF INFLAMMATION-OXIDATIVE STRESS
Glomerular or interstitial inflammation is thought to play an
important role in the initiation of renal fibrosis. Accordingly,
the strategies used were either against inflammation as a
general pathology (corticosteroid treatment) or, more specifi-
cally, against cellular differentiation (fibroblasts, activated
mesangial cells) and/or the proinflammatory agents released
during inflammation (cytokines or chemokines). Treatment
with corticosteroids has been used in some fibrotic nephropa-
thies (IgA) with relative success (3, 39, 64), whereas steroid
treatment had no beneficial effect on patients of African Amer-
ican genetic background with focal segmental glomeruloscle-
rosis (18).
The blockade of fibroblast activation was mainly tested in
experimental forms of nephropathy. Preventive treatment with
an interleukin-1 receptor antagonist or with an anti-intercellu-
lar adhesion molecule-1 (ICAM-1) antibody protected rat kid-
F227
Invited Review
F228 REGRESSION OF RENAL FIBROSIS
neys from the development of fibrosis in the anti-glomerular
basement membrane model of nephropathy (48, 56).
However, when the treatment with anti-ICAM-1 started after
the development of the fibrosis, protection of the renal struc-
ture was rather limited. More recently, an antisense oligodes-
oxynucleotide strategy against ICAM-1 was used to prevent
ischemia-reperfusion injury and to prolong renal isograft sur-
vival in rats (16, 21). Although promising as an approach, there
are several technical problems to be solved before testing of its
applicability to other forms of renal injury and making this
strategy available in humans.
The role of tumor necrosis factor-␣ (TNF-␣) in the progres-
sion of renal scarring (especially in the model of ureteral
obstruction) is well documented (46). Knockout mice for either
the TNFR1 or TNFR2 receptors displayed decreased scores of
collagen IV and matrix expansion compared with wild-type
controls 5 days after unilateral ureteral obstruction (32). The
preservation of renal structure was better when double TNF
receptor knockouts were used and was further increased when
the action of angiotensin II was pharmacologically or geneti-
cally inhibited (33). It is thus interesting to investigate whether
the different techniques of anti-TNF-␣ therapy that have been
lately developed for rheumatoid arthritis (24) can also extend
their field of application to treat renal fibrotic lesions.
The generation of free radicals (reactive oxygen and nitro-
gen species) is considered as initiator of inflammatory response
in a variety of tissues, including the kidney. The link between
oxidative stress and renal infiltration of immune cells in the
kidney has been nicely reviewed recently (62), and we will
avoid unnecessary repetition. We will briefly mention that
treatment with antioxidants gave impressive results concerning
vascular and renal protection in experimental animal models
(regression of vascular remodeling, improvement of endothe-
lial function, inhibition of inflammation, and decrease in blood
pressure). This experimental evidence produced considerable
interest because of the possibilities that therapies targeting
reactive oxygen species might be used against vascular injury
and end-organ damage. However, long-term treatment with
antioxidant vitamins gave disappointing results in large-scale
studies in patients with cardiovascular disease and/or diabetes
(31, 75). It is possible that the current clinically available
antioxidants lack the efficacy necessary for use in long-term
treatments. It is also possible that oxidative stress and inflam-
mation are very important events early in the developing phase
of vascular and renal disease, whereas they participate little
during the established or advanced phases of organ failure. In
this case, the efficiency of an anti-inflammatory or antioxidant
strategy could largely depend on the degree of the evolution of
the disease.
BLOCKADE OF VASOCONSTRICTOR PEPTIDE ACTION
The appearance of renal sclerotic injury and the develop-
ment of renal failure are frequent complications of hyperten-
sion (72). Until recently, the classic role attributed to vasocon-
strictor peptides was that of the “increased pressure effector.”
In this view, the abnormal extracellular matrix formation in
mesangial and vascular smooth muscle cells and the develop-
ment of renal vascular and glomerular sclerosis were pheno-
typic adaptations (remodeling) to the increased tension within
the renal vasculature. However, recent advances in the cellular
AJP-Renal Physiol • VOL
actions of vasoconstrictors indicated that these peptides could
induce, stimulate, or control a variety of cellular pathways in
parallel and/or independently of their constrictor action (such
as cell migration, hypertrophy, proliferation, inflammation,
generation of reactive oxygen species, transactivation of
growth factor receptor) that are directly involved in protein
synthesis and extracellular matrix formation. Two of the most
studied peptides in this field are angiotensin II and endothelin.
The Renin-Angiotensin System
We have presented above the studies in diabetic patients that
gave promising results regarding relative renoprotection by
blocking the renin-angiotensin system. A slight regression of
sclerosis was also observed after long-term treatment with
angiotensin receptor antagonists in the aging rat kidney (53).
The proposed mechanisms involved increased tubular epithe-
lial cell turnover and inhibition of plasminogen activator in-
hibitor-1 (PAI-1) expression. Administration of an angiotensin
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enzyme inhibitor accelerated the obstruction release-induced
regression in the model of unilateral ureteral obstruction (47).
We have addressed the issue of renoprotection by investigating
the mechanisms by which AT1 receptor antagonists make
possible the regression of renal vascular and glomerular fibro-
sis in an experimental model of hypertension-associated renal
failure [nitric oxide (NO) deficiency model] (9). Figure 1
summarizes the results obtained in this study. After 1 mo of
hypertension, renal function severely declined as evidenced by
increased levels of proteinuria and plasma creatinine, and the
mortality rate accounted for 20% of animals. The decline of
renal function was accompanied by an exaggerated gene and
protein expression of transforming growth factor (TGF)-␤,
collagen I, and collagen IV within the renal vasculature and an
abnormal accumulation of extracellular matrix in glomeruli. In
addition, activities of matrix metalloproteinases 2 and 9 were
increased several-fold in glomeruli. At this phase of renal
failure, administration of an angiotensin II receptor antagonist
for 1 wk decreased collagen I, collagen IV, and TGF-␤ gene
and protein expression without affecting the increased level of
metalloproteinases 2 and 9 activities in glomeruli. These cel-
lular alterations were accompanied by a gradual regression of
glomerulosclerosis, a partial restoration of renal function, and
an arrest of mortality. When the antihypertensive treatment
was extended to 1 mo, all cellular, structural, and functional
parameters of the kidney were normalized, indicating that the
progression of renal vascular fibrosis is a reversible process.
Based on these data, we proposed that the mechanism of the
regression was dual: inhibition of the exaggerated synthesis of
extracellular matrix (due to blockade of the angiotensin II-
TGF-␤ pathway) and increased rate of matrix degradation (due
to metalloproteinase activity, probably associated with the
degree of fibrosis and independent of angiotensin blockade).
Subsequently, other investigators confirmed the reversibility of
fibrotic process after angiotensin II blockade in the model of
acute nephronic reduction (1, 2). Eight weeks after surgery,
animals were treated for 1 mo with an angiotensin-converting
enzyme (ACE) inhibitor. Morphological evaluation indicated
regression of preexisting glomerular, tubular, and vascular
lesions and reversal of glomerular hypertrophy. The decreased
number of podocytes, following renal ablation, was not re-
stored by the pharmacological treatment, suggesting that glo-
289 • AUGUST 2005 • www.ajprenal.org
 Invited Review
REGRESSION OF RENAL FIBROSIS F229

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Fig. 1. Prolonged deficiency of endogenous nitric oxide [induced by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME)] is associated
with the development of renal failure. Four weeks of L-NAME treatment produced a dramatic increase in proteinuria and creatininemia that was accompanied
by increased levels of collagen I, transforming growth factor (TGF)-␤, and matrix metalloproteinases (MMPs) in renal vessels and glomeruli. Treatment of the
animals with an angiotensin receptor blocker (ARB; losartan) normalized renal function and reversed renal fibrosis by a dual mechanism: inhibition of collagen
synthesis (ANG II, TGF-␤ dependent) and degradation of extracellular matrix (MMP activity dependent). Adapted from Ref. 9.

merular regeneration largely depends on the degree of damage
of glomerular podocytes. In agreement to this notion, mesan-
gial proliferation was reduced and interstitial changes were
reversed after favorable treatment, whereas the number of
sclerotic glomeruli remained unchanged in biopsies of IgA
nephropathy patients (39).
Endothelin
Endothelin is also an important mediator of vascular and
renal fibrosis (4, 15, 37, 67, 70) (Fig. 2). The aforementioned
studies, performed in a variety of experimental models, dem-
onstrated that endothelin gene and/or protein expression is
increased during nephropathy and colocalizes with fibrotic
lesions. Inversely, pharmacological antagonism of endothelin
receptors delayed the evolution and/or prevented renal failure.
We investigated the efficiency of endothelin receptor antago-
nism to treat renal failure in the NO deficiency model. This
model was applied in a transgenic strain of mice harboring the
firefly luciferase reporter gene under the control of the pro-
moter of the ␣2 chain, the collagen type I gene (12). Due to the
sensitivity of reporter gene assays, changes in the expression of
the collagen I gene were detected in a highly sensitive manner

Fig. 2. ANG II-dependent signaling pathways producing phe-

notypic changes in vascular, endothelial, mesangial, and epi-
thelial cells and leading to glomerular remodeling and to
alterations of renal structure and function. ET-1, endothelin-1;
PAI-1, plasminogen activator inhibitor-1; DAG, diacylglyc-
erol; IP3, inositol 1,4,5-trisphosphate.

AJP-Renal Physiol • VOL 289 • AUGUST 2005 • www.ajprenal.org

Invited Review
F230 REGRESSION OF RENAL FIBROSIS

(8, 15). Because mice displayed slower kinetics compared with
rats for the development of hypertension and renal fibrosis, the
induction of the pathology and the therapeutic treatment lasted
longer (20 and 10 wk, respectively) (7). Endothelin receptor
antagonism, introduced after the appearance of fibrotic lesions,
reduced mortality, partially decreased the abnormal collagen
formation within the renal vasculature by inhibiting collagen I
gene activation, and did not alter the increased levels of blood
pressure. The treated animals displayed a less severe degree of
glomerular lesions even compared with those at the beginning
of the treatment, thus suggesting that renal vascular fibrosis
could regress independently of the systemic hemodynamics
(7). In subsequent studies, we investigated whether repair of
endothelial dysfunction could restore renal failure in this
model. Reactivation of endogenous NO synthesis substantially
improved blood pressure and renal structure, suggesting that
correction of the initiating cause (NO inhibition) could also be
an efficient therapy (Placier S, Boffa JJ, Chatziantoniou C, and
Dussaule JC, unpublished observations).
agent. BMP-7 is highly expressed in the kidney, and its genetic
deletion in mice leads to severe impairment of eye, skeletal,
and kidney development (38). Preventive or curative treatment
with BMP-7 preserved or restored renal histology and renal
function in a rat model of unilateral ureteral obstruction; these
effects of BMP-7 were slightly better compared with the
protection obtained with an ACE inhibitor (40, 55). In addition,
systemic administration of recombinant human BMP-7 led to
repair severely damaged renal tubular epithelial cells and to
improve renal function and survival in mice with nephrotoxic
serum nephritis and in two genetic models for chronic renal
injury and fibrosis (mice deficient in the ␣3-chain of type IV
collagen and MRL/MpJlpr/lpr lupus mice) (76, 77). These
improvements were attributed to the decreased synthesis of
profibrotic molecules and to the increased activity of matrix
metalloproteinase (MMP) 2. These results indicate the poten-
tial of BMP-7 to reverse the TGF-␤-induced injury and to
repair renal tissue in a variety of experimental models.
An additional endogenous peptide antagonizing the effects

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INHIBITION OF TGF-␤ ACTION
TGF-␤ is an agent promoting extracellular matrix synthesis
and is considered to play a major role as mediator of the
fibrogenic action of several vasoconstrictor peptides, especially
that of angiotensin II (10) (Fig. 2). Initially, the strategy aimed
to block the action of TGF-␤ at the systemic (decorin, blocking
anti-body) or receptor (soluble receptors) level. To this end,
preventive protocols gave encouraging results: exogenous ad-
ministration of decorin or prolonged infusion of anti-TGF-␤
antibody protected rat kidneys from the development of glo-
merulonephritis (11), and genetically engineered overexpres-
sion of decorin in the skeletal muscle of rats inhibited the
fibrogenic action of TGF-␤ and protected kidneys against
glomerulosclerosis (41). Alternatively, use of soluble receptors
of TGF-␤ prevented the development of renal and cardiac
fibrosis (45, 71). However, these approaches presented impor-
tant limitations (increased concentrations of decorin lack the
anti-TGF-␤ specificity and can produce secondary effects,
whereas the cost and method of delivery, intravenous infusion,
of soluble receptors make long-term treatment unrealistic) that
tempered the initial enthusiasm and did not allow their exten-
sion to curative protocols.
For these reasons, strategies have been proposed using
agents that target the signaling pathway of TGF-␤ and block its
fibrogenic action. Bone morphogenic protein-7 (BMP-7) and
HGF are two among these systems that have been tested
experimentally in vivo. BMP-7, a 35-kDa homodimeric protein
and member of the TGF-␤ superfamily that antagonizes the
action of TGF-␤, has been used with success as antifibrotic
of TGF-␤ is the HGF. The therapeutic potential of HGF has
been reviewed recently (52). We will briefly mention that
delayed administration of recombinant HGF retarded the pro-
gression of renal lesions by blunting the myofibroblast accu-
mulation and collagen deposition within the kidney. This
action of HGF is likely related to a mitogen-activated protein
kinase-dependent blockade of TGF-␤-induced nuclear translo-
cation of SMADs (73, 74). Continuous infusion of HGF in the
rat remnant kidney model decreased tubulointerstitial collagen
deposition and renal fibrosis; in contrast, blocking endogenous
HGF by an anti-HGF neutralizing antibody increased intersti-
tial collagen and the severity of renal fibrosis. Interestingly,
HGF infusion increased, and conversely HGF antibody sup-
pressed, the in situ gelatinolytic activity in remnant kidneys,
thus supporting the hypothesis that activation of MMP2 and 9
plays a protective role against renal fibrosis (29).
PROMISING STRATEGIES WAITING TO BE TESTED
The above-mentioned strategies (summarized on Table 1)
are variations targeting a common axis: vasoconstrictor-TGF-
␤-induced fibrosis. To date, they are the only ones that have
demonstrated their efficiency in inducing a reversal of fibrosis
in experimental models. However, alternative approaches have
been proposed over the last few years that appear to act
independently of the vasoconstrictor-TGF-␤ fibrotic pathway.
These strategies gave impressive results in preventing progres-
sion and renal structural and functional alterations. Neverthe-
less, it remains to be tested whether they will be efficient in
promoting regression. In the following sections, we will present
some of these promising (but not tested yet) hypotheses.

Table 1. Therapeutic strategies that regressed renal fibrosis and improved renal function
Model Treatment Species Reference(s)

5/6 Nephrectomy Angiotensin II inhibition Rat 1, 2

L-NAME Angiotensin II antagonism Rat 9
Ureteral obstruction Angiotensin II inhibition Rat 47
Aging Angiotensin II antagonism Rat 53
L-NAME Endothelin antagonism Transgenic mouse 7
Nephrotoxic serum nephritis BMP-7 Mouse 77
L-NAME, NG-L-arginine methyl ester; BMP-7, bone morphometric protein-7.

AJP-Renal Physiol • VOL 289 • AUGUST 2005 • www.ajprenal.org


REGRESSION OF RENAL FIBROSIS
Tyrosine Kinase Receptors of Growth Factors
A relatively novel concept regarding the signaling pathways
of potent vasoconstrictors is that they can phosphorylate the
receptors of growth factors (5) (Fig. 2). Increased expression or
activation of these receptors has been observed during the
development of several forms of nephropathies (46), thus
making attractive the hypothesis that this activation could
participate in the progression of renal fibrotic disease. To this
end, nuclease-resistant, high-affinity aptamers that neutralized
the effects of PDGF-B inhibited glomerular and interstitial
fibrosis in a rat model of mesangioproliferative glomeruloscle-
rosis (59). We tested the interaction among vasoconstrictors,
epidermal growth factor (EGF) receptor transactivation, and
the collagen I gene, and we found that endothelin induced a
rapid phosphorylation of the EGF receptor that mediated col-
lagen I gene activation in the renal cortex. Moreover, we
observed that EGF receptor was activated within glomeruli
concomitantly with the development of glomerulosclerosis in
the NO deficiency model. Use of an EGF receptor-tyrosine
kinase inhibitor in a preventive way normalized MAPK acti-
vation, inhibited the abnormal increase in collagen I gene
expression, decreased proteinuria and creatininemia, and pre-
vented the development of renal vascular and glomerular
fibrosis (26, 28). From these studies it appears that blockade or
antagonism of growth factors offers an interesting perspective
on a therapeutic strategy against fibrosis. However, an eventual
problem for transfer to humans is the side effect(s) of such
treatments. The well-known toxicity of long-term blockade of
growth factor action probably excludes life-long treatment.
Thus it is more conceivable to combine them for a short period
with “traditional” chronic renoprotective therapy.
Stabilization of the Extracellular Matrix
Anchorage and stabilization of the extracellular matrix are
other steps that can eventually serve as the targets for thera-
peutic intervention. Tissue transglutaminase 2 belongs to the
enzymes contributing to the stabilization of the extracellular
matrix by forming ␥-glutamyl-lysine cross-linking. Its activa-
tion was observed within the renal tissue in two experimental
models of renal fibrosis (subtotal nephrectomy and diabetic
nephropathy) (43, 65). Subsequent studies observed a several-
fold increase in tissue transglutaminase expression in human
renal biopsy samples from a range of chronic renal diseases
(42). It is possible that inhibition of transglutaminase activity
will make the matrix more fragile and thus easier to degrade
the abnormal extracellular matrix. Supporting this notion, a
specific inhibitor of tissue transglutaminase normalized glu-
cose-induced deposition of extracellular matrix proteins in
renal proximal tubular epithelial cells (66). It would be inter-
esting to test whether a similar effect can be produced in vivo.
Integrins are considered as extracellular matrix receptors.
Expansion of mesangial matrix and podocyte foot process
effacement were attenuated in Alport mice that were also null
for integrin-␣1 expression (17). In addition, fibronectin accu-
mulation and binding to integrin ␣5␤1 were reduced and
glomerular sclerotic lesions were attenuated by heparin treat-
ment in a murine model of lupus nephritis (69). Interestingly,
integrin-␤4, one of the genes involved in cell-cell contact,
showed differential regulation in inflammation and fibrosis in
tubulointerstitial samples from routine renal biopsies. In addi-
AJP-Renal Physiol • VOL
Invited Review
F231
tion, clinical follow-up revealed a correlation between gene
expression data and the progression of renal disease and
allowed segregation of the biopsies into progressive or stable
disease course based on gene expression profiles (35). Binding
of the extracellular matrix is, however, a complex process
requiring participation of several families of proteins that are
also essential for many physiological properties of cells. In-
hibiting collagen I, collagen III, or fibronectin anchorage, for
instance, would have a therapeutic sense if a specific receptor
(or receptor-like protein) could be found and if the inhibition of
the binding with this inhibitor does not alter normal cell
functions.
Degradation of Extracellular Matrix Components
Extracellular matrix degradation is another complex process
in which the family of MMPs plays a major role. Several recent
studies correlated the development of renal fibrosis with acti-
vation of metalloproteinases (34, 63). Studies testing the effi-
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ciency of MMP inhibitor treatment during renal fibrosis gave
contradictory results. The initially proposed antibiotics such as
tetracyclin and doxycyclin as inhibitors of MMPs lack the
necessary specificity. Administration of a more specific met-
alloproteinase inhibitor (batimastat) significantly reduced cyst
number and kidney weight in the (cy/⫹) rat model of autoso-
mal-dominant polycystic kidney disease (57). In contrast, ba-
timastat had no protective effect in the renal ische-
mia-reperfusion injury model in rats (78). As noted above, our
data suggested an antifibrotic-protective role of MMPs in the
NG-nitro-L-arginine methyl ester model (9). The recent obser-
vations that MMPs can cleave other than collagen proteins (50)
and that participate in vascular remodeling (49) make the issue
even more complex. Thus the debate continues as to whether
MMPs are or are not beneficial for regression of fibrosis, and
additional studies are necessary to define the role of MMP in
renal fibrosis.
Agents Associated with Angiotensin II Action: Plasminogen
Activator Inhibitor-1 and Aldosterone
PAI-1, an enzyme inhibiting the plasminogen proteolysis to
plasmin, also reduces MMP activation; increased PAI-1 levels
have been observed in experimental nephropathies or during
aging (22, 53). Inversely, genetic invalidation of PAI-1 expres-
sion protected animals from the development of vascular or
renal interstitial fibrosis (44, 58). The activation of PAI-1
during fibrotic mechanisms appears to be due to the action of
angiotensin II, and treatment with angiotensin inhibitors or
receptor antagonists was accompanied by decreased levels of
PAI-1 within the kidney (27). Based on these results, several
investigators have proposed to inhibit PAI-1 as a means of
treating renal fibrosis. However, PAI-1 null mice displayed a
worse degree of renal failure in the anti-glomerular basement
membrane model, indicating that PAI-1 plays a more complex
role (36).
Until recently, aldosterone has been considered as a rela-
tively minor component of angiotensin-induced fibrogenic ac-
tion. Recent studies, however, suggested that inhibition of
aldosterone could have a direct nephroprotective effect inde-
pendently of angiotensin II. Thus early administration of an-
tagonists of aldosterone receptors prevented glomerular dam-
age and proteinuria in the stroke-prone spontaneously hyper-
289 • AUGUST 2005 • www.ajprenal.org
Invited Review
F232 REGRESSION OF RENAL FIBROSIS
tensive rat (61), 5⁄6 nephrectomy (30), radiation injury (14),
aldosterone/salt-induced hypertension (6), cyclosporine A-in-
duced nephrotoxicity (25), and unilateral ureteral obstruction
(68) models in rodents. It would be interesting to test the
efficiency of aldosterone blockade in curative protocols and to
compare this action (if any) to ACE inhibition or angiotensin
receptor blockade.
SALIENT QUESTIONS AND AREAS FOR FUTURE RESEARCH
The above-presented studies indicate that impressive progress
has been made in our understanding of the mechanisms control-
ling progression and regression of renal fibrosis. From these
studies, however, emerged several new and important questions
that need to be addressed in future research. One of the most
challenging is the link between reversal of fibrosis and refunction
of the kidney; in other words, is it enough to eliminate the
excessive accumulation of extracellular matrix protein to make
nephrons work well again? Or, is there a “no-return point” and, if
so, how can we define this point? Although most investigators
agree that the no-return point is directly associated to podocyte
loss, there is no clear definition of the irreversible stage in terms
of quantity (number of podocytes), quality (kind of functional or
phenotype alteration), and exclusivity (interactions with other
renal cells). Each of these axes of definition raises numerous other
questions: can the irreversible loss of function be attributed to the
disappearance or (inversely) to overexpression of a cytoskeletal or
structural protein? Is the loss of other renal structures (for in-
stance, glomerular or interstitial capillaries) reparable? How can
injured tubular epithelial cells recover? Do they require the re-
cruitment of differentiating or stem cells? We don’t believe that
the above-raised questions will remain unanswered for a long
period, given the state-of-the-art techniques that are available to
investigators today (genetically engineered animals, genomics,
proteomic analysis).
Fig. 3. Progression and regression of renal fibrosis are dynamic processes under the control of profibrotic (right) and antifibrotic (left) systems. Strategies that
gave promising results as preventive treatments but have yet to be tested for their curative efficiency are the final 5 entries at the bottom right.
AJP-Renal Physiol • VOL
CLINICAL PERSPECTIVES
Contrary to the initial belief in nonrepaired damage, the
reversibility of renal fibrosis and the associated improvement
of renal function have been clearly demonstrated in several
experimental models. Figure 3 summarizes the factors that
have been implied in the development of renal fibrosis and its
regression. In human nephropathies, however, the actual treat-
ments target mainly blood pressure control and do not seem
capable of offering more relief than a delay in the rate of
progression. For this reason, it is very important to combine
novel treatments targeting specifically fibrogenesis with classic
antihypertensive agents. Among the strategies that have been
explored over the last few years, those antagonizing the fibrotic
action of TGF-␤ appear to give the most promising results.
Additional studies elucidating some puzzling issues of progres-
sion-regression are still necessary to advance our knowledge.
A key issue is the existence and the definition of a no-return
point. The current belief is consistent with the notion that the
Downloaded from ajprenal.physiology.org on August 4, 2010
no-return point is associated with phenotypic alterations of
podocytes. If so, it is important to identify its molecular,
cellular, and mechanistic characteristics and to try to find
markers detecting or, even better, predicting these alterations
as early as possible.
The following lines, extracted from the poem “Stopping By
Woods on a Snowy Evening,” by Robert Frost, could apply to
the issue of treating chronic renal failure and regressing fibrosis
on the eve of the 21st century:
The woods are lovely, dark, and deep,
But I have promises to keep,
And miles to go before I sleep,
And miles to go before I sleep
Although it would be difficult to predict the length of the road
remaining, the recently emerging data leave no doubt that
promises will be kept.
289 • AUGUST 2005 • www.ajprenal.org

REGRESSION OF RENAL FIBROSIS
GRANTS
This work was financially supported by the Institut National de la Santé et
de la Recherche Médicale and the Faculté de Médecine St. Antoine.
REFERENCES
1. Adamczak M, Gross ML, Amann K, and Ritz E. Reversal of glomerular
lesions involves coordinated restructuring of glomerular microvasculature.
J Am Soc Nephrol 15: 3063–3072, 2004.
2. Adamczak M, Gross ML, Krtil J, Koch A, Tyralla K, Amann K, and
Ritz E. Reversal of glomerulosclerosis after high-dose enalapril treatment
in subtotally nephrectomized rats. J Am Soc Nephrol 14: 2833–2842,
2003.
3. Ando Y, Moriyama T, Oka K, Takatsuji K, Miyazaki M, Akagi Y,
Kawada N, Isaka Y, Izumi M, Yokoyama K, Yamauchi A, Horio M,
Ando A, Ueda N, Sobue K, Imai E, and Hori M. Enhanced interstitial
expression of caldesmon in IgA nephropathy and its suppression by
glucocorticoid-heparin therapy. Nephrol Dial Transplant 14: 1408 –1417,
1999.
4. Benigni A, Zoja C, Corna D, Orisio S, Facchinetti D, Benati L, and
Remuzzi G. Blocking both type A and B endothelin receptors in the
kidney attenuates renal injury and prolongs survival in rats with remnant
kidney. Am J Kidney Dis 27: 416 – 423, 1996.
5. Berk BC. Angiotensin II signal transduction in vascular smooth muscle:
pathways activated by specific tyrosine kinases. J Am Soc Nephrol 10,
Suppl 11: S62–S68, 1999.
6. Blasi ER, Rocha R, Rudolph AE, Blomme EA, Polly ML, and McMa-
hon E. Aldosterone/salt induces renal inflammation and fibrosis in hyper-
tensive rats. Kidney Int 63: 1791–1800, 2003.
7. Boffa JJ, Tharaux PL, Dussaule JC, and Chatziantoniou C. Regression
of renal vascular fibrosis by endothelin receptor antagonism. Hypertension
37: 490 – 496, 2001.
8. Boffa JJ, Tharaux PL, Placier S, Ardaillou R, Dussaule JC, and
Chatziantoniou C. Angiotensin II activates collagen type I gene in the
renal vasculature of transgenic mice during inhibition of nitric oxide
synthesis: evidence for an endothelin-mediated mechanism. Circulation
100: 1901–1908, 1999.
9. Boffa JJ, Ying L, Placier S, Stefanski A, Dussaule JC, and Chatzi-
antoniou C. Regression of renal vascular and glomerular fibrosis: role of
angiotensin II receptor antagonism and metalloproteinases. J Am Soc
Nephrol 14: 1132–1144, 2003.
10. Border WA and Noble NA. Interactions of transforming growth factor-␤
and angiotensin II in renal fibrosis. Hypertension 31: 181–188, 1998.
11. Border WA, Noble NA, Yamamoto T, Harper JR, Yamaguchi Y,
Pierschbacher MD, and Ruoslahti E. Natural inhibitor of transforming
growth factor-␤ protects against scarring in experimental kidney disease.
Nature 360: 361–364, 1992.
12. Bou-Gharios G, Garrett LA, Rossert J, Niederreither K, Eberspae-
cher H, Smith C, Black C, and de Crombrugghe B. A potent far-
upstream enhancer in the mouse pro␣2(I) collagen gene results expression
of reporter genes in transgenic mice. J Cell Biol 134: 1333–1344, 1996.
13. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE,
Parving HH, Remuzzi G, Snapinn SM, Zhang Z, and Shahinfar S.
Effects of losartan on renal and cardiovascular outcomes in patients with
type 2 diabetes and nephropathy. N Engl J Med 345: 861– 869, 2001.
14. Brown NJ, Nakamura S, Ma L, Nakamura I, Donnert E, Freeman M,
Vaughan DE, and Fogo AB. Aldosterone modulates plasminogen acti-
vator inhibitor-1 and glomerulosclerosis in vivo. Kidney Int 58: 1219 –
1227, 2000.
15. Chatziantoniou C, Boffa JJ, Ardaillou R, and Dussaule JC. Nitric
oxide inhibition induces early activation of type I collagen gene in renal
resistance vessels and glomeruli in transgenic mice: role of endothelin.
J Clin Invest 101: 2780 –2789, 1998.
16. Chen W, Bennett CF, Wang ME, Dragun D, Tian L, Stecker K, Clark
JH, Kahan BD, and Stepkowski SM. Perfusion of kidneys with unfor-
mulated “naked” intercellular adhesion molecule-1 antisense oligode-
oxynucleotides prevents ischemic/reperfusion injury. Transplantation 68:
880 – 887, 1999.
17. Cosgrove D, Rodgers K, Meehan D, Miller C, Bovard K, Gilroy A,
Gardner H, Kotelianski V, Gotwals P, Amatucci A, and Kalluri R.
Integrin ␣1␤1 and transforming growth factor-␤1 play distinct roles in
Alport glomerular pathogenesis and serve as dual targets for metabolic
therapy. Am J Pathol 157: 1649 –1659, 2000.
AJP-Renal Physiol • VOL 289 • AUGUST 2005 •
Invited Review
F233
18. Crenshaw G, Bigler S, Salem M, and Crook ED. Focal segmental
glomerulosclerosis in African Americans: effects of steroids and angio-
tensin converting enzyme inhibitors. Am J Med Sci 319: 320 –325, 2000.
19. Delanian S, Porcher R, Balla-Mekias S, and Lefaix JL. Randomized,
placebo-controlled trial of combined pentoxifylline, and tocopherol for
regression of superficial radiation-induced fibrosis. J Clin Oncol 21:
2545–2550, 2003.
20. Diez J, Querejeta R, Lopez B, Gonzalez A, Larman M, and Martinez
Ubago JL. Losartan-dependent regression of myocardial fibrosis is asso-
ciated with reduction of left ventricular chamber stiffness in hypertensive
patients. Circulation 105: 2512–2517, 2002.
21. Dragun D, Lukitsch I, Tullius SG, Qun Y, Park JK, Schneider W,
Luft FC, and Haller H. Inhibition of intercellular adhesion molecule-1
with antisense deoxynucleotides prolongs renal isograft survival in the rat.
Kidney Int 54: 2113–2122, 1998.
22. Eddy A and Giachelli CM. Renal expression of genes that promote
interstitial inflammation and fibrosis in rats with protein-overload protein-
uria. Kidney Int 47: 1546 –1557, 1995.
23. Farci P, Roskams T, Chessa L, Peddis G, Mazzoleni AP, Scioscia R,
Serra G, Lai ME, Loy M, Caruso L, Desmet V, Purcell RH, and
Balestrieri A. Long-term benefit of interferon ␣ therapy of chronic
hepatitis D: regression of advanced hepatic fibrosis. Gastroenterology
Downloaded from ajprenal.physiology.org on August 4, 2010
126: 1740 –1749, 2004.
24. Feldmann M. Development of anti-TNF therapy for rheumatoid arthritis.
Nature Rev Immunol 2: 364 –371, 2002.
25. Feria I, Pichardo I, Juarez P, Ramirez V, Gonzalez MA, Uribe N,
Garcia-Torres R, Lopez-Casillas F, Gamba G, and Bobadilla NA.
Therapeutic benefit of spironolactone in experimental chronic cyclospor-
ine A nephrotoxicity. Kidney Int 63: 43–52, 2003.
26. Flamant M, Tharaux PL, Placier S, Henrion D, Coffman T, Chatzi-
antoniou C, and Dussaule JC. Epidermal growth factor transactivation
mediates the tonic and fibrogenic effects of endothelin in the aortic wall of
transgenic mice. FASEB J 17: 327–329, 2003.
27. Fogo AB. Renal fibrosis and the renin-angiotensin system. Adv Nephrol
Necker Hosp 31: 69 – 87, 2001.
28. François H, Placier S, Flamant M, Tharaux PL, Chansel D, Dussaule
JC, and Chatziantoniou C. Prevention of renal vascular and glomerular
fibrosis by epidermal growth factor receptor inhibition. FASEB J 18:
926 –928, 2004.
29. Gong R, Rifai A, Tolbert EM, Centracchio JN, and Dworkin LD.
Hepatocyte growth factor modulates matrix metalloproteinases and plas-
minogen activator/plasmin proteolytic pathways in progressive renal in-
terstitial fibrosis. J Am Soc Nephrol 14: 3047–3060, 2003.
30. Greene EL, Kren S, and Hostetter TH. Role of aldosterone in the
remnant kidney model in the rat. J Clin Invest 98: 1063–1068, 1996.
31. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Mio-
cardico. Dietary supplementation with n-3 polyunsaturated fatty acids and
vitamin E after myocardial infarction: results of the GISSI-Prevenzione
trial. Lancet 354: 447– 455, 1999.
32. Guo G, Morrissey J, McCracken R, Tolley T, and Klahr S. Role of
TNFR1 and TNFR2 receptors in tubulointerstitial fibrosis of obstructive
nephropathy. Am J Physiol Renal Physiol 277: F766 –F772, 1999.
33. Guo G, Morrissey J, McCracken R, Tolley T, Liapis H, and Klahr S.
Contributions of angiotensin II and tumor necrosis factor-␣ to the devel-
opment of renal fibrosis. Am J Physiol Renal Physiol 280: F777–F785,
2001.
34. Hayashi K, Horikoshi S, Osada S, Shofuda K, Shirato I, and Tomino
Y. Macrophage-derived MT-1 MMp and increased MMP-2 activity are
associated with glomerular damage in crescentic glomerulonephritis.
J Pathol 191: 299 –305, 2000.
35. Henger A, Kretzler M, Doran P, Bonrouhi M, Schmid H, Kiss E,
Cohen CD, Madden S, Porubsky S, Grone EF, Schlondorff D, Nelson
PJ, and Grone HJ. Gene expression fingerprints in human tubulointer-
stitial inflammation and fibrosis as prognostic markers of disease progres-
sion. Kidney Int 65: 904 –917, 2004.
36. Hertig A, Berrou J, Allory Y, Breton L, Commo F, Costa De Beau-
regard MA, Carmeliet P, and Rondeau E. Type 1 plasminogen activator
inhibitor deficiency aggravates the course of experimental glomerulone-
phritis through overactivation of transforming growth factor-␤. FASEB J
17: 1904 –1906, 2003.
37. Hocher B, Thöne-Reineke C, Rohmeiss P, Schmager F, Slowinski T,
Burst V, Siegmund F, Quertermous T, Bauer C, Neumayer HH,
Schleuning WD, and Theuring F. Endothelin-1 transgenic mice devel-
www.ajprenal.org
Invited Review
F234 REGRESSION OF RENAL FIBROSIS
ops glomerulosclerosis, interstitial fibrosis, and renal cysts but not hyper-
tension. J Clin Invest 99: 1380 –1389, 1997.
38. Hogan BL. Bone morphogenic proteins in development. Curr Opin Genet
Dev 6: 432– 438, 1996.
39. Hotta O, Furuta T, Chiba S, Tomioka S, and Taguma Y. Regression of
IgA nephropathy: a repeat biopsy study. Am J Kidney Dis 39: 493–502,
2002.
40. Hruska KA, Guo G, Wozniak M, Martin D, Miller S, Liapis H,
Loveday K, Klahr S, Sampath TK, and Morrissey J. Osteogenic
protein-1 prevents renal fibrogenesis associated with ureteral obstruction.
Am J Physiol Renal Physiol 279: F130 –F143, 2000.
41. Isaka Y, Brees D, Ikegaya K, Kaneda Y, Imai E, Noble NA, and
Border WA. Gene therapy by skeletal muscle expression of decorin
prevents fibrotic disease in rat kidney. Nat Med 2: 418 – 423, 1996.
42. Johnson TS, El-Koraie AF, Skill NJ, Baddour NM, El Nahas AM,
Njloma M, Adam AG, and Griffin M. Tissue transglutaminase and the
progression of human renal scarring. J Am Soc Nephrol 14: 2052–2062, 2003.
43. Johnson TS, Skill NJ, El Nahas AM, Oldroyd SD, Thomas GL,
Douthwaite JA, Haylor JL, and Griffin M. Transglutaminase transcrip-
tion and antigen translocation in experimental renal scarring. J Am Soc
Nephrol 10: 2146 –2157, 1999.
44. Kaikita K, Fogo AB, Ma L, Schoenhard JA, Brown NJ, and Vaughan
DE. Plasminogen activator inhibitor-1 deficiency prevents hypertension
and vascular fibrosis in response to long-term nitric oxide synthase
inhibition. Circulation 104: 839 – 844, 2001.
45. Kasuga H, Ito Y, Sakamoto S, Kawachi H, Shimizu F, Yuzawa Y, and
Matsuo S. Effects of anti-TGF-␤ type II receptor antibody on experimen-
tal glomerulonephritis. Kidney Int 60: 1745–1755, 2001.
46. Klahr S and Morrissey JJ. The role of vasoactive compounds, growth
factors and cytokines in the progression of renal disease. Kidney Int Suppl
75: S7–S14, 2000.
47. Koo JW, Kim Y, Rozen S, and Mauer M. Enalapril accelerates remod-
eling of the renal interstitium after release of unilateral ureteral obstruction
in rats. J Nephrol 16: 203–209, 2003.
48. Lan HY, Nikolic-Paterson DJ, Zarama M, Vannice JL, and Atkins
RC. Suppression of experimental crescentic glomerulonephritis by the
interleukin-1 receptor antagonist. Kidney Int 43: 479 – 485, 1993.
49. Lehoux S, Lemarie CA, Esposito B, Lijnen HR, and Tedgui A.
Pressure-induced matrix metalloproteinase-9 contributes to early hyper-
tensive remodeling. Circulation 109: 1041–1047, 2004.
50. Lelongt B, Bengatta S, Delauche M, Lund LR, Werb Z, and Ronco
PM. Matrix metalloproteinase 9 protects mice from anti-glomerular base-
ment membrane nephritis through its fibrinolytic activity. J Exp Med 193:
793– 802, 2001.
51. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB,
Ritz E, Atkins RC, Rohde R, and Raz I, Collaborative Study Group.
Renoprotective effect of the angiotensin-receptor antagonist irbesartan in
patients with nephropathy due to type 2 diabetes. N Engl J Med 345:
851– 860, 2001.
52. Liu Y. Hepatocyte growth factor in kidney fibrosis: therapeutic potential and
mechanisms of action. Am J Physiol Renal Physiol 287: F7–F16, 2004.
53. Ma LJ, Nakamura S, Whitsitt JS, Marcantoni C, Davidson JM, and
Fogo AB. Regression of sclerosis in aging by an angiotensin inhibition-
induced decrease in PAI-1. Kidney Int 58: 2425–2436, 2000.
54. Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M,
Ponticelli C, Ritz E, and Zucchelli P. Effect of the angiotensin-convert-
ing-enzyme inhibitor benazepril on the progression of chronic renal
insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progres-
sive Renal Insufficiency Study Group. N Engl J Med 334: 939 –945, 1996.
55. Morrissey J, Hruska K, Guo G, Wang S, Chen Q, and Klahr S. Bone
morphogenetic protein-7 improves renal fibrosis and accelerates the return
of renal function. J Am Soc Nephrol 13, Suppl 1: S14 –S21, 2002.
56. Nishikawa K, Guo YJ, Miyasaka M, Tamatani T, Collins AB, Sy MS,
McCluskey RT, and Andres G. Antibodies to intercellular adhesion mole-
cule 1/lymphocyte function-associated antigen 1 prevent crescent formation in
rat autoimmune glomerulonephritis. J Exp Med 177: 667– 677, 1993.
57. Obermuller N, Morente N, Kranzlin B, Gretz N, and Witzgall R. A
possible role for metalloproteinases in renal cyst development. Am J
Physiol Renal Physiol 280: F540 –F550, 2001.
58. Oda T, Jung YO, Kim HS, Cai X, Lopez-Guisa JM, Ikeda Y, and
Eddy AA. PAI-1 deficiency attenuates the fibrogenic response to ureteral
obstruction. Kidney Int 60: 587–596, 2001.
59. Ostendorf T, Kunter U, Grone HJ, Bahlmann F, Kawachi H, Shimizu
F, Koch KM, Janjic N, and Floege J. Specific antagonism of PDGF
AJP-Renal Physiol • VOL 289 • AUGUST 2005 •
prevents renal scarring in experimental glomerulonephritis. J Am Soc
Nephrol 12: 909 –918, 2001.
60. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen
S, and Arner P. The effect of irbesartan on the development of diabetic
nephropathy in patients with type 2 diabetes. N Engl J Med 345: 870 – 878,
2001.
61. Rocha R, Chander PN, Khanna K, Zuckerman A, and Stier CT.
Mineralocorticoid blockade reduces vascular injury in stroke-prone hyper-
tensive rats. Hypertension 31: 451– 458, 1998.
62. Rodriguez-Iturbe B, Varzir ND, Herrera-Acosta J, and Johnson RJ.
Oxidative stress, renal infiltration of immune cells, and salt-sensitive
hypertension: all for one and one for all. Am J Physiol Renal Physiol 286:
F606 –F616, 2004.
63. Shiozawa S. Participation of macrophage in glomerular sclerosis through
the expression and activation of matrix metalloproteinases. Pathol Int 50:
441– 457, 2000.
64. Shoji T, Nakanishi I, Suzuki A, Hayashi T, Togawa M, Okada N, Imai
E, Hori M, and Tsubakihara Y. Early treatment with corticosteroids
ameliorates proteinuria, proliferative lesions, and mesangial phenotypic
modulation in adult diffuse proliferative IgA nephropathy. Am J Kidney
Dis 35: 194 –201, 2000.
65. Skill NJ, Griffin M, El Nahas AM, Sanai T, Haylor JL, Fisher M,
Downloaded from ajprenal.physiology.org on August 4, 2010
Jamie MF, Mould NN, and Johnson TS. Increases in renal ⑀-(␥-
glutamyl)-lysine crosslinks result from compartment-specific changes in
tissue transglutaminase in early experimental diabetic nephropathy: patho-
logic implications. Lab Invest 81: 705–716, 2001.
66. Skill NJ, Johnson TS, Coutts IG, Saint RE, Fisher M, Huang L, El
Nahas AM, Collighan RJ, and Griffin M. Inhibition of transglutaminase
activity reduces extracellular matrix accumulation induced by high glu-
cose levels in proximal tubular epithelial cells. J Biol Chem 279: 47754 –
47762, 2004.
67. Tharaux PL, Chatziantoniou C, Casellas D, Fouassier L, Ardaillou R,
and Dussaule JC. Vascular endothelin-1 gene expression, synthesis and
effect on renal type I collagen synthesis and nephroangiosclerosis during
nitric oxide synthase inhibition in rats. Circulation 99: 2185–2191, 1999.
68. Trachtman H, Weiser AC, Valderrama E, Morgado M, and Palmer
LS. Prevention of renal fibrosis by spironolactone in mice with complete
unilateral ureteral obstruction. J Urol 172: 1590 –1594, 2004.
69. Van Vliet A, van Alderwegen I, Baelde H, de Heer E, and Bruijn JA.
Fibronectin accumulation in glomerulosclerotic lesions: self-assembly
sites and the heparin II binding domain. Kidney Int 61: 481– 489, 2002.
70. Verhagen AM, Rabelink TJ, Braam B, Opgenorth TJ, Grone HJ,
Koomans HA, and Joles JA. Endothelin A receptor blockade alleviates
hypertension and renal lesions associated with chronic nitric oxide syn-
thase inhibition. J Am Soc Nephrol 9: 755–762, 1998.
71. Wang B, Hao J, Jones SC, Yee MS, Roth JC, and Dixon IM. Decreased
Smad 7 expression contributes to cardiac fibrosis in the infarcted rat heart.
Am J Physiol Heart Circ Physiol 282: H1685–H1696, 2002.
72. Weistuch JM and Dworkin LD. Does essential hypertension cause end-
stage renal disease? Kidney Int 41: S33–S37, 1992.
73. Yang J, Dai C, and Liu Y. Hepatocyte growth factor suppresses renal
interstitial myofibroblast activation and intercepts Smad signal transduc-
tion. Am J Pathol 163: 621– 632, 2003.
74. Yang J and Liu Y. Delayed administration of hepatocyte growth factor
reduces renal fibrosis in obstructive nephropathy. Am J Physiol Renal
Physiol 284: F349 –F357, 2003.
75. Yusuf S, Dagenais G, Pogue J, Bosch J, and Sleight P. Vitamin E
supplementation and cardiovascular events in high-risk patients: the Heart
Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342:
154 –160, 2000.
76. Zeisberg M, Bottiglio C, Kumar N, Maeshima Y, Strutz F, Muller GA,
and Kalluri R. Bone morphogenic protein-7 inhibits progression of
chronic renal fibrosis associated with two genetic mouse models. Am J
Physiol Renal Physiol 285: F1060 –F1067, 2003.
77. Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz
F, and Kalluri R. BMP-7 counteracts TGF-␤1-induced epithelial-to-
mesenchymal transition and reverses chronic renal injury. Nat Med 9:
964 –968, 2003.
78. Ziswiler R, Daniel C, Franz E, and Marti HP. Renal matrix metallo-
proteinase activity is unaffected by experimental ischemia-reperfusion
injury and matrix metalloproteinase inhibition does not alter outcome of
renal function. Exp Nephrol 9: 118 –124, 2001.
www.ajprenal.org