Insights into the mechanisms of renal fibrosis: is it possible to achieve regression
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《美国生理学杂志》
Institut National de la Santé et de la Recherche Médicale Unité , Hpital Tenon, and AP-HP, Laboratoire de Physiologie, Faculté de Médecine St. Antoine, Paris, France
ABSTRACT
Recent evidence suggests that the progression of renal fibrosis is a reversible process, at least in experimental models. The present review summarizes the new insights concerning the mechanisms of progression and regression of renal disease and examines this novel evidence under the light of feasibility and transfer to human nephropathies. 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 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 established in other tissues, such as heart, liver, and skin (19, 20, 23). Because renal fibrosis appears irrespective of the underlying 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, nephrosclerosis, polycystic kidney disease, or diabetic nephropathy) (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 systemic and local actions of angiotensin II in kidneys. Despite these promising results, the challenge remains to go beyond slowing down the progression and to try to achieve regression of renal fibrosis and restoration of renal structure. The formation 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 proteinases. 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 regression 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 specifically, 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 nephropathies (IgA) with relative success (3, 39, 64), whereas steroid treatment had no beneficial effect on patients of African American genetic background with focal segmental glomerulosclerosis (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-intercellular adhesion molecule-1 (ICAM-1) antibody protected rat kidneys 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 structure was rather limited. More recently, an antisense oligodesoxynucleotide strategy against ICAM-1 was used to prevent ischemia-reperfusion injury and to prolong renal isograft survival 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 progression 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 genetically 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 nitrogen 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 endothelial 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 inflammation 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 development of renal failure are frequent complications of hypertension (72). Until recently, the classic role attributed to vasoconstrictor 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 development of renal vascular and glomerular sclerosis were phenotypic adaptations (remodeling) to the increased tension within the renal vasculature. However, recent advances in the cellular 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 epithelial cell turnover and inhibition of plasminogen activator inhibitor-1 (PAI-1) expression. Administration of an angiotensin 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 fibrosis 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 cellular 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 restored by the pharmacological treatment, suggesting that glomerular regeneration largely depends on the degree of damage of glomerular podocytes. In agreement to this notion, mesangial 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, demonstrated 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 antagonism 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 promoter 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 (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).
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 administration of decorin or prolonged infusion of anti-TGF- antibody protected rat kidneys from the development of glomerulonephritis (11), and genetically engineered overexpression 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 important 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 extension 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 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 potential 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 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 progression of renal lesions by blunting the myofibroblast accumulation 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 translocation 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 interstitial collagen and the severity of renal fibrosis. Interestingly, HGF infusion increased, and conversely HGF antibody suppressed, 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 progression and renal structural and functional alterations. Nevertheless, 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.
View this table:
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 glomerulosclerosis (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 collagen 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 activation, inhibited the abnormal increase in collagen I gene expression, decreased proteinuria and creatininemia, and prevented 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 therapeutic intervention. Tissue transglutaminase 2 belongs to the enzymes contributing to the stabilization of the extracellular matrix by forming -glutamyl-lysine cross-linking. Its activation 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 glucose-induced deposition of extracellular matrix proteins in renal proximal tubular epithelial cells (66). It would be interesting 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 accumulation and binding to integrin 51 were reduced and glomerular sclerotic lesions were attenuated by heparin treatment 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 addition, 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. Inhibiting 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 activation of metalloproteinases (34, 63). Studies testing the efficiency 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 metalloproteinase inhibitor (batimastat) significantly reduced cyst number and kidney weight in the (cy/+) rat model of autosomal-dominant polycystic kidney disease (57). In contrast, batimastat had no protective effect in the renal ischemia-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 observations 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 expression 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 relatively minor component of angiotensin-induced fibrogenic action. Recent studies, however, suggested that inhibition of aldosterone could have a direct nephroprotective effect independently of angiotensin II. Thus early administration of antagonists of aldosterone receptors prevented glomerular damage and proteinuria in the stroke-prone spontaneously hypertensive rat (61), nephrectomy (30), radiation injury (14), aldosterone/salt-induced hypertension (6), cyclosporine A-induced 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 controlling 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 instance, glomerular or interstitial capillaries) reparable How can injured tubular epithelial cells recover Do they require the recruitment 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).
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 treatments 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 progression-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 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.
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.
FOOTNOTES
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ABSTRACT
Recent evidence suggests that the progression of renal fibrosis is a reversible process, at least in experimental models. The present review summarizes the new insights concerning the mechanisms of progression and regression of renal disease and examines this novel evidence under the light of feasibility and transfer to human nephropathies. 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 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 established in other tissues, such as heart, liver, and skin (19, 20, 23). Because renal fibrosis appears irrespective of the underlying 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, nephrosclerosis, polycystic kidney disease, or diabetic nephropathy) (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 systemic and local actions of angiotensin II in kidneys. Despite these promising results, the challenge remains to go beyond slowing down the progression and to try to achieve regression of renal fibrosis and restoration of renal structure. The formation 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 proteinases. 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 regression 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 specifically, 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 nephropathies (IgA) with relative success (3, 39, 64), whereas steroid treatment had no beneficial effect on patients of African American genetic background with focal segmental glomerulosclerosis (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-intercellular adhesion molecule-1 (ICAM-1) antibody protected rat kidneys 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 structure was rather limited. More recently, an antisense oligodesoxynucleotide strategy against ICAM-1 was used to prevent ischemia-reperfusion injury and to prolong renal isograft survival 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 progression 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 genetically 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 nitrogen 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 endothelial 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 inflammation 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 development of renal failure are frequent complications of hypertension (72). Until recently, the classic role attributed to vasoconstrictor 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 development of renal vascular and glomerular sclerosis were phenotypic adaptations (remodeling) to the increased tension within the renal vasculature. However, recent advances in the cellular 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 epithelial cell turnover and inhibition of plasminogen activator inhibitor-1 (PAI-1) expression. Administration of an angiotensin 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 fibrosis 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 cellular 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 restored by the pharmacological treatment, suggesting that glomerular regeneration largely depends on the degree of damage of glomerular podocytes. In agreement to this notion, mesangial 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, demonstrated 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 antagonism 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 promoter 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 (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).
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 administration of decorin or prolonged infusion of anti-TGF- antibody protected rat kidneys from the development of glomerulonephritis (11), and genetically engineered overexpression 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 important 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 extension 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 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 potential 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 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 progression of renal lesions by blunting the myofibroblast accumulation 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 translocation 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 interstitial collagen and the severity of renal fibrosis. Interestingly, HGF infusion increased, and conversely HGF antibody suppressed, 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 progression and renal structural and functional alterations. Nevertheless, 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.
View this table:
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 glomerulosclerosis (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 collagen 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 activation, inhibited the abnormal increase in collagen I gene expression, decreased proteinuria and creatininemia, and prevented 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 therapeutic intervention. Tissue transglutaminase 2 belongs to the enzymes contributing to the stabilization of the extracellular matrix by forming -glutamyl-lysine cross-linking. Its activation 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 glucose-induced deposition of extracellular matrix proteins in renal proximal tubular epithelial cells (66). It would be interesting 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 accumulation and binding to integrin 51 were reduced and glomerular sclerotic lesions were attenuated by heparin treatment 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 addition, 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. Inhibiting 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 activation of metalloproteinases (34, 63). Studies testing the efficiency 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 metalloproteinase inhibitor (batimastat) significantly reduced cyst number and kidney weight in the (cy/+) rat model of autosomal-dominant polycystic kidney disease (57). In contrast, batimastat had no protective effect in the renal ischemia-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 observations 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 expression 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 relatively minor component of angiotensin-induced fibrogenic action. Recent studies, however, suggested that inhibition of aldosterone could have a direct nephroprotective effect independently of angiotensin II. Thus early administration of antagonists of aldosterone receptors prevented glomerular damage and proteinuria in the stroke-prone spontaneously hypertensive rat (61), nephrectomy (30), radiation injury (14), aldosterone/salt-induced hypertension (6), cyclosporine A-induced 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 controlling 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 instance, glomerular or interstitial capillaries) reparable How can injured tubular epithelial cells recover Do they require the recruitment 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).
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 treatments 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 progression-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 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.
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.
FOOTNOTES
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