Skip to main content
NCBI home page
International Journal of Experimental Pathology logoLink to International Journal of Experimental Pathology
. 2004 Feb;85(1):1–11. doi: 10.1111/j.0959-9673.2004.00376.x

Progression and regression in renal vascular and glomerular fibrosis

Christos Chatziantoniou 1, Jean-Jacques Boffa 1, Pierre-Louis Tharaux 1, Martin Flamant 1, Pierre Ronco 1, Jean-Claude Dussaule 1
PMCID: PMC2517455  PMID: 15113389

Abstract

End-stage renal disease (ESRD) is characterized by the development of fibrotic lesions in the glomerular, interstitial and vascular compartments. Renal fibrogenesis, a common complication of diabetes and hypertension, is a complex dynamic process involving several players such as inflammatory agents, cytokines, vasoactive agents and enzymes participating in extracellular matrix assembly, anchoring or degradation. The only available treatment today against chronic renal failure is dialysis or kidney transplantation, making thus ESRD one of the most expensive diseases to treat on a per-patient basis. An emerging challenge for clinicians, maybe the nephrologist's Holy Grail in the 21st century, is to stop definitively the decline of renal function and, if possible, to achieve regression of renal fibrosis and restoration of renal structure. Over the last 5 years, different approaches have been tested in experimental models of nephropathy with variable degree of success. In this review, we will focus on the mechanisms of the hypertension-associated fibrosis and the few recent studies that gave promising results for a therapeutic intervention.

Keywords: angiotensin II, collagen I, progression, regression, renal vascular remodelling

Diabetes and hypertension are amongst the leading causes of end-stage renal failure (ESRF), accounting for more than 60% of new cases (United States Renal Data System 1998; Valderrabano et al. 1996). Kidney disease can also develop from infection, inflammation of renal blood vessels and glomeruli, kidney stones and cysts. ESRF is characterized by the development of fibrotic lesions in the glomerular, interstitial and vascular compartments. These lesions are defined by the abnormal accumulation of extracellular matrix (mainly fibrillar collagens) that substitutes normal kidney structure. Under normal conditions, the formation of extracellular matrix is a dynamic equilibrium between systems that promote its synthesis and those that favour its degradation. In pathophysiological conditions that lead to the development of fibrosis, this equilibrium is broken due to exaggerated rates of extracellular matrix synthesis, to diminished capacity of degradation or to a combination of both. This process appears irrespective of the underlying disease and originating compartment, pointing out a final common pathway, independently of the primary cause. Under this view, identifying and targeting the systems participating in this pathway may provide an efficient treatment against renal fibrosis and failure regardless of the initiating pathology. Over the last years, an important progress has been made towards this direction, and it is now well established that various therapeutic interventions can prevent the development of renal damage in several experimental models. The challenge, however, remains to go beyond slowing down the decline of renal function, and to attempt to achieve regression of renal fibrosis and restoration of the renal structure. Our group has contributed to the understanding of the fibrotic mechanisms by focusing on experimental models in which renal fibrosis originates from vascular dysfunction. The present work aimed to review some of the most significant recent developments concerning the mechanisms of progression and regression of renal fibrosis.

Progression of renal fibrosis of vascular origin

One of the most common complications associated with hypertension is the development of renal sclerotic injury (Weistuch & Dworkin 1992). For several years, the general belief was that renal vascular and glomerular sclerosis were consequences of the high blood pressure and that the exaggerated extracellular matrix formation in mesangial and vascular smooth muscle cells was an adaptive response to the increased tension within the renal vasculature (Figure 1). This hypothesis postulates that the systemic blood pressure increase is transmitted within renal resistance vessels and glomeruli initiating an adaptive mechanism that is subsequently extended to renal interstitium and that ultimately leads to the development of renal fibrosis. Under this schema, circulating or locally generated vasoconstrictors have a primary (if not exclusive) action on the blood pressure increase. However, over the last years, this belief was evolved to the concept that vasoconstrictors have fibrogenic effects independently of their constrictor action (Figure 1) and that an efficient treatment against hypertension and its complications should also address the issue of pathological structural remodelling (in addition to simply lowering blood pressure). This concept is based on data obtained mainly in the cardiac tissue with blockers of the renin–angiotensin system (Weber 2000). The following lines will examine whether this concept can also apply to the renal vasculature; the focus will be on the data concerning the fibrogenic action of the most extensively studied peptides in this field, angiotensin II, and endothelin and of the beneficial effects of their inhibitors or antagonists; in addition, it will be examined whether inhibitors of the different growth factors (considered to mediate the fibrogenic action of vasoconstrictors) such as transforming growth factor-β (TGFβ) and tyrosine kinase growth factors can be used against renal fibrosis.

Figure 1.

Figure 1

Open in a new tab

Classically, the development of renal fibrosis of vascular origin was considered as an adaptive response to blood pressure increase. This notion has been challenged lately by the concept that vasoactive agents can control extracellular martrix synthesis through a genetic action independent of their constrictor effects.

Angiotensin II

A central role for the renin–angiotensin system in the vascular remodelling and fibrosis is well established. Its involvement in renal fibrosis was suggested from studies using pharmacological blockade of the angiotensin II action. Thus, inhibition of the angiotensin-converting enzyme (ACE) or antagonism of the angiotensin AT1 receptors slowed or stopped the progression of renal fibrosis in several models of experimental or genetic hypertension. In the nitric oxide (NO) deficiency model of hypertension (L-NAME model) for instance, inhibition or antagonism of angiotensin II preserved kidney function and morphology in addition to normalizing systolic pressure (Casellas et al. 1999; Michel et al. 1996). Treatment with a calcium blocker and/or an ACE inhibitor improved renal haemodynamics and protected against nephrosclerosis in spontaneously hypertensive rat (SHR) treated with L-NAME (Francischetti et al. 1998). To understand the underlying cellular mechanism(s), we examined the hypothesis of whether angiotensin II specifically activates genes of extracellular matrix proteins (such as collagen I) within the renal cortical vasculature (Boffa et al. 1999). To this end, we used a transgenic strain of mice harbouring two reporter genes, the firefly luciferase and the Escherichia coli B-galactosidase, under the control of the promoter of the α2-chain of mouse collagen type I gene. The choice of these mice was based on data showing that the expression pattern of the two reporter genes closely correlated with cell and tissue distribution of collagen I (Bou-Gharios et al. 1996; Chatziantoniou et al. 1998). Due to the sensibility of reporter gene assays, this model allows changes in the expression of the collagen I gene to be detected in a highly sensitive manner. Thus, the sensitivity and reproducibility of luciferase activity measurements provided us with accurate estimates of tissular (afferent arterioles or glomeruli vs. heart and aorta) and temporal (before, during and after the establishment of pathology) activation of collagen I gene. Hypertension and renal failure were induced in these mice by inhibiting endogenous NO synthesis in presence or absence of angiotensin blockade for a period of up to 14 weeks (Boffa et al. 1999). Systolic blood pressure was increased after 6 weeks of treatment and reached a plateau after 10 weeks (around 160 mmHg). Collagen I gene activity was increased in freshly isolated afferent arterioles and glomeruli earlier than systolic pressure (4 weeks of L-NAME treatment), indicating that the two phenomena could be controlled by distinct mechanisms. The activation of collagen I gene became more pronounced with time, and at 14 weeks, increased 10-fold compared with controls in afferent arterioles and glomeruli. This activation of collagen I gene was accompanied by the progressive accumulation of extracellular matrix within glomeruli as evidenced by classical morphological methods. The kinetics of collagen I gene activation was different in aorta and heart; it remained unchanged up to 8 weeks and was increased slowly thereafter (in parallel with the systolic pressure increase), suggesting that the early activation of collagen I gene in renal resistance vessels and glomeruli was specific to the renal tissue (Chatziantoniou et al. 1998). Pharmacological blockade of angiotensin II action inhibited collagen I gene activation in the renal cortical tissue and prevented the development of renal vascular and glomerular fibrosis. This study, summarized in Figure 2, provided an in vivo evidence that angiotensin II is involved in the fibrogenic process by inducing collagen gene activation within the renal tissue by a cellular mechanism(s) partly independent of its systemic haemodynamic actions (Boffa et al. 1999).

Figure 2.

Figure 2

Open in a new tab

Antagonism of angiotensin II action inhibited collagen I gene activation within the renal vasculature (glomeruli and afferent arterioles) and prevented the development of glomerulosclerosis without normalizing systolic pressure increase (Boffa et al. 1999).

Endothelin

Several recent studies point to a major role for endothelin in mediating renal fibrosis. Transgenic mice overexpressing human endothelin 1 gene developed glomerulosclerosis and interstitial fibrosis without change in arterial pressure (Hocher et al. 1997); conversely, selective blockade of ETA receptors prevented proteinuria and glomerular ischaemia and blunted the degree of vascular and tubulointerstitial injuries during inhibition of NO synthesis without normalizing blood pressure (Verhagen et al. 1998). These results corroborate the hypothesis that the endothelin-mediated fibrogenic mechanisms are independent of systemic haemodynamics. We have observed that mRNA expression and peptide content of endothelin in renal resistance vessels and endothelin urinary excretion rate were increased in rats developing renal vascular fibrosis (Tharaux et al. 1999). We pursued the hypothesis of an endothelin–collagen I gene interaction using the same transgenic strain and a similar to the above-described protocol with the exception that an endothelin receptor blocker was used instead of the AT1 receptor antagonist. Endothelin blockade prevented the collagen I gene activation and protected kidneys from the development of fibrosis without altering the blood pressure increase induced by NO inhibition (Chatziantoniou et al. 1998). These studies provided an additional support to the hypothesis that the fibrogenic action of vasoactive peptides is local and independent of systemic haemodynamics; on the other hand, these findings raised a number of important questions such as to identify the way (if any) of the interaction between angiotensin II and endothelin that leads to collagen I gene activation and the development of renal fibrosis. We have addressed this issue in subsequent experiments by investigating the role of some pro-fibrogenic and/or mitogenic transduction pathways that are known to interact with angiotensin II, such as TGF-β/SMAD, MAP/ERK and tyrosine kinase receptors of growth factors.

TGF-β

TGF-β is a well-known agent promoting extracellular matrix synthesis and is considered to play a major role as mediator of the fibrogenic action of several vasoconstrictor peptides, particularly of the angiotensin II (Border & Noble 1998). The angiotensin II–TGF-β interaction does not appear to depend on systemic haemodymamics. In the L-NAME model, TGF-β mRNA expression was increased locally in the renal cortex; treatment with an ACE inhibitor, but not with hydralazine, reduced the exaggerated expression of TGF-β and improved renal histology, despite a similar reduction of systolic blood pressure with both treatments (Kashiwagi et al. 2000). More controversial is the issue of whether TGF-β mediates the fibrogenic actions of endothelin. In two models of experimental fibrotic nephropathy (the streptozotocin-induced diabetes or the 5/6 nephrectomy), ETA/B antagonism had no effect on the exaggerated expression of TGF-β or collagen IV and the progression of fibrosis in glomeruli and tubules (Kelly et al. 2000). In other studies that used similar models of chronic renal failure (5/6 nephrectomy), ETA/B antagonism markedly reduced extracellular matrix synthesis, protected renal structure and improved the survival of 5/6 nephrectomized rats (Benigni et al. 1993). We studied the interactions between angiotensin II, endothelin and TGF-β on collagen I gene activation in acute in vivo experiments. To this end, we tested whether exogenous administration of angiotensin II, endothelin or TGF-β activated collagen I gene in the aortic and renal cortical tissue and whether a cross-reaction of blockers of these systems affected collagen I gene activation (Fakhouri et al. 2001). The main conclusion of these studies was that cooperation and/or synergy between endothelin and TGF-β are required and mediate the fibrogenic action of angiotensin II. The molecular events that lead from the angiotensin II receptor to collagen I gene activation were subsequently examined by focusing on the role of MAPK pathway.

MAP kinases and intracellular signalling mediators of fibrogenesis

The MAP/ER kinase cascade is considered as a major intracellular signalling pathway mediating the mitogenic actions of most vasoconstrictors. We tested if this pathway could also mediate fibrogenesis in the renal and vascular tissues in collagen I gene transgenic mice. Angiotensin II produced an early stimulation of collagen I gene activity in freshly isolated aortas and renal cortical slices followed by similar increase in collagen I gene mRNA levels (Tharaux et al. 2000). This effect of angiotensin II was inhibited by AT1 receptor antagonism and blockade of the MAPK/ERK cascade, but not by inhibition of the P38 kinase pathway or blockade of the transcription factor NFκB. The angiotensin II-induced increase of the MAPK/ERK activity was accompanied by increased expression of the c-fos proto-oncogene; inversely, inactivation of the transcriptional factor AP-1 cancelled the effect of angiotensin II on the collagen I gene (Figure 3). Similar data have been obtained in a transgenic model of rat harbouring both human renin and angiotensinogen genes (Muller et al. 2000). In this model, characterized by angiotensin II–induced end-organ damage in heart and kidney, AP-1 expression and several genes regulated by this complex (such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) were locally overexpressed in the renal and cardiac tissues; treatment with angiotensin II or endothelin antagonists, but not with hydralazine, improved albuminuria and renal injury and reduced mortality rates; these functional improvements were independent of blood pressure effects and were associated to significant reduction of AP-1 (and AP-1-regulated genes) expression in the kidney.

Figure 3.

Figure 3

Open in a new tab

Angiotensin II-induced signalling pathways that lead to activation of collagen I gene. Interruption of one of these cascades is sufficient to inhibit collagen I synthesis and to prevent the development of fibrosis (dash arrows indicate the targets used in experimental studies to block collagen I formation).

Tyrosine kinase receptors of growth factors

A relatively novel concept regarding the signalling pathways of potent vasoconstrictors such as angiotensin II or endothelin is that they can transactivate the receptors of growth factors (Berk 1999). Increased expression or levels, or activation of these receptors have been observed during the development of several forms of nephropathies (Klahr & Morrisey 2000), making thus attractive the hypothesis that this activation could participate in the progression of renal fibrotic disease. To this end, a tyrosine kinase inhibitor attenuated the development of fibrosis in the model of unilateral ureteral obstruction (Ludewig et al. 2000). More recently, use of nuclease resistant high-affinity aptamers that neutralized the effects of PDGF-B inhibited glomerular and interstitial fibrosis in a rat model of mesangioproliferative glomerulosclerosis (Ostendorf et al. 2001). We tested the interaction between vasoconstrictors, epidermal growth factor (EGF) receptor transactivation and collagen I gene (Flamant et al. 2003), and we found that endothelin induced a rapid phosphorylation of the EGF receptor associated to activation of the MAP/ERK pathway and to increased collagen I gene activity in freshly isolated aortic and renal cortical tissue (Figure 3). In subsequent in vivo studies, we observed that EGF receptor was activated within glomeruli concomitantly to the development of glomerulosclerosis in the NO deficiency model. In this model, an EGF receptor-tyrosine kinase inhibitor, normalized the MAPK activation, inhibited the abnormal increase of collagen I gene expression, decreased proteinuria and creatininaemia and prevented the development of renal vascular and glomerular fibrosis (Franşois et al. 2003). It appears, thus, that EGF receptor activation is a major step in the fibrogenic process, at least in the model of NO deficiency. These observations provide a novel perspective for the eventual use of growth factor receptor inhibitors as anti-fibrotic agents.

Regression of renal fibrosis

Blockade of the renin–angiotensin system

Figure 3 summarizes the signalling pathways that have been characterized by our studies as mediators of the angiotensin II-induced activation of collagen I gene. These studies were mainly focused on the mechanisms leading to the progression of renal vascular fibrosis. From a therapeutic point of view, however, the challenge remains to go beyond prevention and to attempt to achieve regression of renal fibrosis and restoration of the renal structure. Over the last years, several studies in humans gave promising results indicating that anti-hypertensive treatments can have beneficial effects regarding renoprotection. Thus, blockade of the angiotensin II action protected against the progression of renal insufficiency in patients with various renal diseases (such as glomerulopathies, interstitial nephritis, nephrosclerosis, polycystic kidney disease or diabetic nephropathy) (Maschio et al. 1996). This initial report was validated with the publication of three large-scale studies concerning hypertensive patients with type 2 diabetes (Brenner et al. 2001; Lewis et al. 2001; Parving et al. 2001). Angiotensin II receptor antagonism was effective in protecting against the progression of nephropathy by reducing microalbuminuria and slowing down the rate of decline of filtration rate; interestingly, these renoprotective effects were independent of the blood-pressure-lowering effect, providing an additional argument supporting the dissociation between the contractile and the fibrotic actions of angiotensin II in the renal tissue. These observations are corroborated by a morphometric analysis performed in a limited number of type 2 diabetic patients with glomerulosclerosis. After 2 years of follow-up, mean cortical interstitial fractional volume (a marker of progression of renal fibrosis) was increased significantly in the placebo group, whereas it remained unchanged in the ACE inhibitor-treated patients (Cordonnier et al. 1999).

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 (Boffa et al. 2003). To this end, hypertension and renal failure were induced by inhibiting NO synthesis. After 1 month of hypertension, animals displayed a decline of renal function (evidenced by increased levels of proteinuria and plasma creatinine), an exaggerated gene and protein expression of TGF-β, collagen I and collagen IV within the renal vasculature and an abnormal accumulation of extracellular matrix in glomeruli (Figure 4). These structural and functional alterations were accompanied by increased activities of matrix metalloproteinases (MMPs) 2 and 9. Administration of an angiotensin II receptor antagonist immediately decreased collagen I, collagen IV and TGF-β gene and protein expressions, without affecting activities of metalloproteinases 2 and 9. These cellular alterations were accompanied by a gradual regression of glomerulosclerosis and restoration of renal function; after 1 month of anti-hypertensive treatment, all functional and structural parameters of kidney were normalized (Figure 4). Hydralazine failed to improve renal function and/or structure despite a similar degree of systolic pressure decrease, providing another element to support the hypothesis that systemic pressure regulation and renal vascular fibrosis follow distinct mechanisms. These data are among the first studies implying that the progression of renal vascular fibrosis is a reversible process. The mechanism of the regression (at least in the NO deficiency model) appears to be dual: inhibition of collagen synthesis due to AT1 receptor antagonism and activation of metalloproteinases that is probably associated with the degree of fibrosis independently of AT1 blockade. In a subsequent study, other investigators confirmed the reversibility of vascular lesions after angiotensin II blockade in the model of 5/6 nephrectomy (Adamczak et al. 2003). In this study, delayed treatment with an ACE inhibitor regressed preexisting glomerular, tubular and vascular lesions, and reversed glomerular hypertrophy. However, the initially decreased number of podocytes (following renal ablation) was not restored by the pharmacological treatment indicating that the limiting step of glomerular regeneration depends on the degree of damage of glomerular podocytes. In agreement to this notion, mesangial proliferation was reduced and interstitial changes were reversed after favourable treatment, whereas the number of sclerotic glomeruli remained unchanged in biopsies of immunoglobulin A (IgA) nephropathy patients (Hotta et al. 2002). These observations are consistent with the notion that the no-return point is associated to podocyte alterations and underline the importance of finding markers to detect these alterations as early as possible.

Figure 4.

Figure 4

Open in a new tab

Chronic inhibition of nitric oxide is accompanied by the development of renal failure as evidenced by the increase of urinary protein excretion, plasma creatinine and the exaggerated extracellular matrix accumulation in renal cortex. Treatment of the diseased animals with an angiotensin receptor antagonist normalized renal functional and structural parameters indicating that renal fibrosis is a reversible phenomenon, at least in this experimental model (white, black and grey bars represent control animals and animals treated for 4 weeks with L-NAME or 4 weeks with L-NAME followed by 4 weeks L-NAME + losartan, respectively; L-NAME: a NO synthase inhibitor; Los: losartan, an AT1 receptor antagonist; w: weeks (Boffa et al. 2003).

Blockade of the TGF-β pathway

Despite the reservations, exposed in the first part of the review, of whether TGF-β is a common fibrogenic mediator of all vasoconstrictor peptides, its involvement in the angiotensin II-induced fibrogenesis is well established. For this reason, anti-fibrogenic strategies have been proposed that block the action of TGF-β. Exogenous administration of decorin mimicked the effect of chronic anti-TGF-β antibody infusion by blunting the formation of extracellular matrix within the renal cortex and protecting rat kidneys from the development of glomerulonephritis (Border et al. 1992). In addition, endogenous overexpression of decorin in the skeletal muscle of rats by gene transfer technology inhibited the fibrogenic action of TGF-β and protected kidneys against glomerulosclerosis (Isaka et al. 1996). However, an important limitation for the generalized use of decorin is that increased concentrations of decorin lack the anti-TGF-β specificity and can produce secondary effects. An alternative approach could be to block the TGF-β action at the receptor level (exogenous administration of anti-TGF-β receptor antibody or soluble receptors of TGF-β) or at the intracellular signalling pathway (SMADs, the intracellular mediators of TGF-β actions); both treatments gave promising results by preventing the development of renal and cardiac fibrosis (Kasuga et al. 2001; Wang et al. 2002).

Another more recent option is to use bone morphogenic protein-7 (BMP-7), a 35-kDa homodimeric protein and a member of the TGF-β superfamily that antagonizes the action of TGF-β. BMP-7 is highly expressed in the kidney, and its genetic deletion in mice leads to severe impairment of eye, skeletal and kidney development (Hogan 1996). Ischaemic kidneys showed a marked decrease of BMP-7 mRNA, whereas BMP-7 enhanced recovery when infused into rats with ischaemia-induced acute renal failure (Simon et al. 1999). More importantly, BMP-7 treatment in a preventive or curative way 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 to the protection obtained with an ACE inhibitor (Hruska et al. 2000; Morrissey et al. 2002). In addition, systemic administration of recombinant human BMP-7 in mice with nephrotoxic serum nephritis leads to repair of severely damaged renal tubular epithelial cells, in association with reversal of chronic renal injury (Zeisberg et al. 2003). These results indicate the potential of BMP-7 to reverse the TGF-β-induced injury and to repair renal tissue in a variety of experimental models.

An additional endogenous ligand antagonizing the effects of TGF-β is the ‘Hepatocyte Growth Factor’ (HGF). The therapeutic potential of HGF has been tested in the unilateral ureteral obstruction model, a model of renal interstitial fibrosis (Yang & Liu 2003). 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 probably related to a mitogen-activated protein kinase-dependent blockade of TGF-β-induced nuclear translocation of SMADs (Yang et al. 2003). Continuous infusion of HGF in the rat remnant kidney model decreased tubulointerstitial collagen deposition and ameliorated renal fibrosis; in contrast, blocking of endogenous HGF by an anti-HGF-neutralizing antibody increased interstitial collagen and aggravated the degree of renal fibrosis. Interestingly, HGF infusion increased, and conversely HGF antibody suppressed, the in situ gelatinolytic activity in remnant kidneys thus, supporting our hypothesis that MMPs play a beneficial role in renal fibrosis by facilitating collagen degradation (Gong et al. 2003)

Stem cells

A very important issue when one addresses the problem of regression of renal fibrosis is whether sclerotic glomeruli can regenerate, and if so, what cells are or can be used as progenitors. As mentioned above, a limiting step factor for the reversibility of renal fibrosis appears to be podocyte differentiation. Considerable progress has been made over the last years to this direction, and emerging data demonstrated that bone marrow cells can serve as progenitors for a variety of cells such as vascular smooth, endothelial, hepatic or osteoblastic cells (Prockop 1997). Furthermore, it has been demonstrated that these marrow-derived cells can migrate into areas of induced tissue degeneration, undergo differentiation and participate in the regeneration of the damaged tissue (Asahara et al. 1997; Ferrari et al. 1998). This innovative therapeutic approach has been successfully applied in myocardial ischaemia (Kawamoto et al. 2001) and in osteogenesis imperfecta, a genetic disorder in which osteoblasts produce defective type I collagen (Horwitz et al. 1999).

Bone marrow-derived cells may have the potential to differentiate into glomerular mesangial cells (Imasawa et al. 2001). However, this efficiency to differentiate can act as double-edge feature, depending on whether the conditions favour hyperplasia and/or proliferation or recovery and/or regeneration. Thus, the sclerotic phenotype was carried by mesangial cell progenitors, and this phenotype could be derived from the bone marrow in a genetic model of diffuse glomerulosclerosis and glomerular hypertrophy (Cornacchia et al. 2001), or in IgA nephropathy (Imasawa et al. 1999). Inversely, healthy bone marrow cells gave rise to mesangial cells in vivo and participated in the regeneration of glomeruli in the anti-Thy1 antibody-mediated glomerulonephritis (Ito et al. 2001); in addition, use of genetically modified bone marrow-derived cells to deliver an interleukin-1 receptor antagonist prevented the phenotypic alterations of interstitial cells and protected kidneys in the model of unilateral ureteral obstruction (Yamagishi et al. 2001).

Perspectives

Figure 5 summarizes the factors that have been identified to play a crucial role in the mechanisms controlling extracellular matrix formation in the renal vascular and glomerular tissue. Although encouraging data have been obtained lately, the issue still remains open on how to cure renal fibrosis. In this context, some critical steps of the fibrotic mechanisms need to be first well defined. Can the same treatment, for instance, be applied to all stages of renal fibrosis, or does it depend on the degree, severity and nature (type and supramolecular organization of collagen) of lesions? Are all stages of fibrosis reversible or is there a no-return point, and in this case, how this point will be clinically defined and what markers can be used for its definition? Because the abnormal formation of collagens is a common phenomenon of chronic renal failure independently of cause and initiating mechanisms, is it possible to achieve regression by targeting a common step (blocking collagen synthesis)? In that sense, angiotensin II appears as an appropriate target, and the recently obtained data point to this direction. However, anti-angiotensin treatments have been widely used for several years now, and it becomes clear that blocking angiotensin II action alone is not as much efficient in regressing renal fibrosis in humans as it is in animals. Does this mean that the prescribed doses of angiotensin blockers (based on anti-hypertensive efficency) are not sufficient enough to block the locally generated angiotensin? Or, may it be better to associate angiotensin blockade to specific anti-fibrotic treatments (anti-TGF-β or anti-tyrosine kinase growth factors) and/or to agents that can degrade specifically the abnormally formed extracellular matrix? Is it reasonable to believe that the technological advance based on stem cells will permit to reconstruct and regenerate completely a fibrotic kidney, even if it is beyond on what we call today a no-return point? Certainly, it is still a long way to go before making a fibrotic kidney operational again; however, the progress made over the last years and the continuously novel options emerging in the horizon are sufficient reasons for optimism that is not far from the day in which the regression of renal fibrosis will no more considered as a myth but as a reality.

Figure 5.

Figure 5

Open in a new tab

Factors controlling the formation of extracellular matrix and the development of renal vascular and glomerular fibrosis. Inhibition of pro-fibrogenic agents and/or activation of anti-fibrogenic systems have been accompanied by regression of fibrosis and restoration of renal function in experimental nephropathies.

References

  1. Adamczak M, Gross ML, Krtil J, Koch A, Tyralla K, Amann K, Ritz E. Reversal of glomerulosclerosis after high-dose enalapril treatment in subtotally nephrectomized rats. J. Am. Soc. Nephrol. 2003;14:2833–2842. doi: 10.1097/01.asn.0000095248.91994.d3. [DOI] [PubMed] [Google Scholar]
  2. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275:964–967. doi: 10.1126/science.275.5302.964. [DOI] [PubMed] [Google Scholar]
  3. Benigni A, Zoja C, Corna D, Orisio S, Longaretti L, Bertani T, Remuzzi G. A specific endothelin subtype A receptor antagonist protects against injury in renal disease progression. Kidney Int. 1993;44:440–444. doi: 10.1038/ki.1993.263. [DOI] [PubMed] [Google Scholar]
  4. Berk BC. Angiotensin II signal transduction in vascular smooth muscle: pathways activated by specific tyrosine kinases. J. Am.Soc. Nephrol. 1999;10(Suppl. 11):S62–S68. [PubMed] [Google Scholar]
  5. Boffa JJ, Tharaux PL, Placier S, Ardaillou R, Dussaule JC, 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. 1999;100:1901–1908. doi: 10.1161/01.cir.100.18.1901. [DOI] [PubMed] [Google Scholar]
  6. Boffa JJ, Ying L, Placier S, Stefanski A, Dussaule JC, Chatziantoniou C. Regression of renal vascular and glomerular fibrosis: Role of angiotensin II receptor antagonism and metalloproteinases. J. Am. Soc. Nephrol. 2003;14:1132–1144. doi: 10.1097/01.asn.0000060574.38107.3b. (editorial comment 1411–1414) [DOI] [PubMed] [Google Scholar]
  7. Border WA, Noble NA. Interactions of transforming growth factor-β and angiotensin II in renal fibrosis. Hypertension. 1998;31:181–188. doi: 10.1161/01.hyp.31.1.181. [DOI] [PubMed] [Google Scholar]
  8. Border WA, Noble NA, Yamamoto T, Harper JR, Yamaguchi Y, Pierschbacher MD, Ruoslahti E. Natural inhibitor of transforming growth factor-β protects against scarring in experimental kidney disease. Nature. 1992;360:361–364. doi: 10.1038/360361a0. [DOI] [PubMed] [Google Scholar]
  9. Bou-Gharios G, Garrett LA, Rossert J, Niederreither K, Eberspaecher H, Smith C, Black C, de Crombrugghe B. A potent far-upstream enhancer in the mouse proα2 (I) collagen gene regulates expression of reporter genes in transgenic mice. J. Cell Biol. 1996;134:1333–1344. doi: 10.1083/jcb.134.5.1333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl. J. Med. 2001;345:861–869. doi: 10.1056/NEJMoa011161. [DOI] [PubMed] [Google Scholar]
  11. Casellas D, Benhamed S, Artuso A, Jover B. Candesartan and progression of preglomerular lesions in L-NAME hypertensive rats. J. Am. Soc. Nephrol. 1999;10:S230–S233. [PubMed] [Google Scholar]
  12. Chatziantoniou C, Boffa JJ, Ardaillou R, 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. 1998;101:2780–2789. doi: 10.1172/JCI2132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cordonnier DJ, Pinel N, Barro C, Maynard M, Zaoui P, Halimi S, Hurault de Ligny B, Reznic Y, Simon D, Bilous RW. Expansion of cortical interstitium is limited by converting enzyme inhibition in type 2 diabetic patients with glomerulosclerosis. The Diabiopsies Group. J. Am. Soc. Nephrol. 1999;10:1253–1263. doi: 10.1681/ASN.V1061253. [DOI] [PubMed] [Google Scholar]
  14. Cornacchia F, Fornoni A, Plati AR, Thomas A, Wang Y, Inverardi L, Striker LJ, Striker GE. Glomerulosclerosis is transmitted by bone marrow-derived mesangial cell progenitors. J. Clin. Invest. 2001;108:1649–1656. doi: 10.1172/JCI12916. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fakhouri F, Placier S, Ardaillou R, Dussaule JC, Chatziantoniou C. Angiotensin II activates collagen type I gene in the renal cortex and aorta of transgenic mice through interaction with endothelin and TGFβ. J. Am. Soc. Nephrol. 2001;12:2701–2710. doi: 10.1681/ASN.V12122701. [DOI] [PubMed] [Google Scholar]
  16. Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Stornaiuolo A, Cossu G, Mavilio F. Muscle regeneration by bone marrow-derived myogenic progenitors. Science. 1998;279:1528–1530. doi: 10.1126/science.279.5356.1528. [DOI] [PubMed] [Google Scholar]
  17. Flamant M, Tharaux PL, Placier S, Henrion D, Coffman T, Chatziantoniou C, Dussaule JC. Epidermal Growth Factor Transactivation Mediates the Tonic and Fibrogenic Effects of Endothelin in the Aortic Wall of Transgenic Mice. FASEB J. 2003;17:327–329. doi: 10.1096/fj.02-0115fje. (Epub 02–0115fje, December 2002) [DOI] [PubMed] [Google Scholar]
  18. Francischetti A, Ono H, Frohlich ED. Renoprotective effects of felodipine and/or enalapril in spontaneously hypertensive rats with and without L-NAME. Hypertension. 1998;31:795–801. doi: 10.1161/01.hyp.31.3.795. [DOI] [PubMed] [Google Scholar]
  19. Franşois H, Placier S, Parvez-Braun L, Dussaule JC, Chatziantoniou C. Prevention of renal vascular and glomerular fibrosis by inhibiting tyrosine-kinase growth factor receptors. J. Am. Soc. Nephrol. 2003;14:20A. [Google Scholar]
  20. Gong R, Rifai A, Tolbert EM, Centracchio JN, Dworkin LD. Hepatocyte growth factor modulates matrix metalloproteinases and plasminogen activator/plasmin proteolytic pathways in progressive renal interstitial fibrosis. J. Am. Soc. Nephrol. 2003;14:3047–3060. doi: 10.1097/01.asn.0000098686.72971.db. [DOI] [PubMed] [Google Scholar]
  21. Hocher B, Thöne-Reineke C, Rohmeiss P, Schmager F, Slowinski T, Burst V, Siegmund F, Quertermous T, Bauer C, Neumayer HH, Schleuning WD, Theuring F. Endothelin-1 transgenic mice develops glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension. J. Clin. Invest. 1997;99:1380–1389. doi: 10.1172/JCI119297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hogan BL. Bone morphogenic proteins in development Curr. Opin. Genet. Dev. 1996;6:432–438. doi: 10.1016/s0959-437x(96)80064-5. [DOI] [PubMed] [Google Scholar]
  23. Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M, Sussman M, Orchard P, Marx JC, PyeritZ RE, Brenner MK. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat. Med. 1999;5:309–313. doi: 10.1038/6529. [DOI] [PubMed] [Google Scholar]
  24. Hotta O, Furuta T, Chiba S, Tomioka S, Taguma Y. Regression of IgA nephropathy: a repeat biopsy study. Am. J. Kidney Dis. 2002;39:493–502. doi: 10.1053/ajkd.2002.31399. [DOI] [PubMed] [Google Scholar]
  25. Hruska KA, Guo G, Wozniak M, Martin D, Miller S, Liapis H, Loveday K, Klahr S, Sampath TK, Morrissey J. Osteogenic protein-1 prevents renal fibrogenesis associated with ureteral obstruction. Am. J. Physiol. Renal Physiol. 2000;279:F130–F143. doi: 10.1152/ajprenal.2000.279.1.F130. [DOI] [PubMed] [Google Scholar]
  26. Imasawa T, Nagasawa R, Utsunomiya Y, Kawamura T, Zhong Y, Makita N, Muso E, Miyawaki S, Maruyama N, Hosoya T, Sakai O, Ohno T. Bone marrow transplantation attenuates murine IgA nephropathy: The role of a stem cell disorder. Kidney Int. 1999;56:1809–1817. doi: 10.1046/j.1523-1755.1999.00750.x. [DOI] [PubMed] [Google Scholar]
  27. Imasawa T, Utsunomiya Y, Kawamura T, Zhong Y, Nagasawa R, Okabe M, Maruyama N, Hosoya T, Ohno T. The potential of bone marrow-derived cells to differentiate to glomerular mesangial cells. J. Am. Soc. Nephrol. 2001;12:1401–1409. doi: 10.1681/ASN.V1271401. [DOI] [PubMed] [Google Scholar]
  28. Isaka Y, Brees D, Ikegaya K, Kaneda Y, Imai E, Noble NA, Border WA. Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney. Nat. Med. 1996;2:418–423. doi: 10.1038/nm0496-418. [DOI] [PubMed] [Google Scholar]
  29. Ito T, Suzuki A, Imai E, Okabe M, Hori M. Bone marrow is a reservoir of repopulating mesangial cells during glomerular remodeling. J. Am. Soc. Nephrol. 2001;12:2625–2635. doi: 10.1681/ASN.V12122625. [DOI] [PubMed] [Google Scholar]
  30. Kashiwagi M, Shinozaki M, Hirakata H, Tamaki K, Hirano T, Tokumoto M, Goto H, Okuda S, Fujishima M. Locally activated renin-angiotensin system associated with TGFβ as a major factor for renal injury induced by chronic inhibition of nitric oxide synthase in rats. J. Am. Soc. Nephrol. 2000;11:616–624. doi: 10.1681/ASN.V114616. [DOI] [PubMed] [Google Scholar]
  31. Kasuga H, Ito Y, Sakamoto S, Kawachi H, Shimizu F, Yuzawa Y, Matsuo S. Effects of anti-TGF-beta type II receptor antibody on experimental glomerulonephritis. Kidney Int. 2001;60:1745–1755. doi: 10.1046/j.1523-1755.2001.00990.x. [DOI] [PubMed] [Google Scholar]
  32. Kawamoto A, Gwon HC, Iwaguro H, Yamaguchi JI, Uchida S, Masuda H, Silver M, Ma H, Kearney M, Isner JM, Asahara T. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation. 2001;103:634–637. doi: 10.1161/01.cir.103.5.634. [DOI] [PubMed] [Google Scholar]
  33. Kelly DJ, Skinner SL, Gilbert RE, Cox AJ, Cooper ME, Wilkinson-Berka JL. Effects of endothelin or angiotensin II receptor blockade on diabetes in the transgenic (mRen-2), 27 rat. Kidney Int. 2000;57:1882–1894. doi: 10.1046/j.1523-1755.2000.00038.x. [DOI] [PubMed] [Google Scholar]
  34. Klahr S, Morrisey JJ. The role of vasoactive compounds, growth factors and cytokines in the progression of renal disease. Kidney Int. 2000;57(Suppl. 75):S7–S14. [PubMed] [Google Scholar]
  35. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N. Engl. J. Med. 2001;345:851–860. doi: 10.1056/NEJMoa011303. [DOI] [PubMed] [Google Scholar]
  36. Ludewig D, Kosmehl H, Sommer M, Bohmer FD, Stein G. PDGF receptor kinase blocker AG1295 attenuates interstitial fibrosis in rat kidney after unilateral obstruction. Cell Tissue Res. 2000;299:97–103. doi: 10.1007/s004419900118. [DOI] [PubMed] [Google Scholar]
  37. Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N. Engl. J. Med. 1996;334:939–945. doi: 10.1056/NEJM199604113341502. [DOI] [PubMed] [Google Scholar]
  38. Michel JB, Xu Y, Blot S, Philippe M, Chatelier G. Improved survival in rats administered L-NAME due to converting enzyme inhibition. J. Cardiovasc. Pharmacol. 1996;28:142–148. doi: 10.1097/00005344-199607000-00021. [DOI] [PubMed] [Google Scholar]
  39. Morrissey J, Hruska K, Guo G, Wang S, Chen Q, Klahr S. Bone morphogenetic protein-7 improves renal fibrosis and accelerates the return of renal function. J. Am. Soc. Nephrol. 2002;13(Suppl):S14–S21. [PubMed] [Google Scholar]
  40. Muller DN, Mervaala EM, Schmidt F, Park JK, Dechend R, Genersch E, Breu V, Loffler BM, Ganten D, Schneider W, Haller H, Luft FC. Effect of bosentan on NF-κB, inflammation, and tissue factor in angiotensin II-induced end-organ damage. Hypertension. 2000;36:282–290. doi: 10.1161/01.hyp.36.2.282. [DOI] [PubMed] [Google Scholar]
  41. Ostendorf T, Kunter U, Grone HJ, Bahlmann F, Kawachi H, Shimizu F, Koch KM, Janjic N, Floege J. Specific antagonism of PDGF prevents renal scarring in experimental glomerulonephritis. J. Am. Soc. Nephrol. 2001;12:909–918. doi: 10.1681/ASN.V125909. [DOI] [PubMed] [Google Scholar]
  42. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N. Engl. J. Med. 2001;345:870–878. doi: 10.1056/NEJMoa011489. [DOI] [PubMed] [Google Scholar]
  43. Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997;276:71–74. doi: 10.1126/science.276.5309.71. [DOI] [PubMed] [Google Scholar]
  44. Simon M, Maresh JG, Harris SE, HernandeZ JD, Arar M, Olson MS, Abboud HE. Expression of bone morphogenetic protein-7 mRNA in normal and ischemic adult rat kidney. Am. J. Physiol. 1999;276:F382–F389. doi: 10.1152/ajprenal.1999.276.3.F382. [DOI] [PubMed] [Google Scholar]
  45. Tharaux PL, Chatziantoniou C, Casellas D, Fouassier L, Ardaillou R, 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. 1999;99:2185–2191. doi: 10.1161/01.cir.99.16.2185. [DOI] [PubMed] [Google Scholar]
  46. Tharaux PL, Chatziantoniou C, Fakhouri F, Dussaule JC. Angiotensin II activates collagen I gene through a mechanism involving the MAP/ER kinase pathway. Hypertension. 2000;36:330–336. doi: 10.1161/01.hyp.36.3.330. [DOI] [PubMed] [Google Scholar]
  47. United States Renal Data System. Incidence and prevalence of ESRD. Am. J. Kidney Dis. 1998;32(Suppl. 1):S38–S49. doi: 10.1053/ajkd.1998.v32.pm9713406. [DOI] [PubMed] [Google Scholar]
  48. Valderrabano F, Berthoux FC, Jones EH, Mehls O. Report on management of renal failure in Europe, XXV, 1994 end stage renal disease and dialysis report. The EDTA-ERA Registry. Nephrol. Dial. Transplant. 1996;11(Suppl. 1):2–21. doi: 10.1093/ndt/11.supp1.2. [DOI] [PubMed] [Google Scholar]
  49. Verhagen AM, Rabelink TJ, Braam B, Opgenorth TJ, Grone HJ, Koomans HA, Joles JA. Endothelin A receptor blockade alleviates hypertension and renal lesions associated with chronic nitric oxide synthase inhibition. J. Am. Soc. Nephrol. 1998;9:755–762. doi: 10.1681/ASN.V95755. [DOI] [PubMed] [Google Scholar]
  50. Wang B, Hao J, Jones SC, Yee MS, Roth JC, Dixon IM. Decreased Smad 7 expression contributes to cardiac fibrosis in the infarcted rat heart. Am. J. Physiol. Heart Circ. Physiol. 2002;282:H1685–H1696. doi: 10.1152/ajpheart.00266.2001. [DOI] [PubMed] [Google Scholar]
  51. Weber KT. Targeting pathological remodelling: concepts of cardioprotection and reparation. Circulation. 2000;102:1342–1345. doi: 10.1161/01.cir.102.12.1342. [DOI] [PubMed] [Google Scholar]
  52. Weistuch JM, Dworkin LD. Does essential hypertension cause end- stage renal disease? Kidney Int. 1992;41:S33–S37. [PubMed] [Google Scholar]
  53. Yamagishi H, Yokoo T, Imasawa T, Mitarai T, Kawamura T, Utsunomiya Y. Genetically modified bone marrow-derived vehicle cells site specifically deliver an anti-inflammatory cytokine to inflamed interstitium of obstructive nephropathy. J. Immunol. 2001;166:609–616. doi: 10.4049/jimmunol.166.1.609. [DOI] [PubMed] [Google Scholar]
  54. Yang J, Dai C, Liu Y. Hepatocyte growth factor suppresses renal interstitial myofibroblast activation and intercepts Smad signal transduction. Am. J. Pathol. 2003;163:621–632. doi: 10.1016/S0002-9440(10)63689-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Yang J, Liu Y. Delayed administration of hepatocyte growth factor reduces renal fibrosis in obstructive nephropathy. Am. J. Physiol. Renal Physiol. 2003;284:F349–F357. doi: 10.1152/ajprenal.00154.2002. [DOI] [PubMed] [Google Scholar]
  56. Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strut Z F, Kalluri R. BMP-7 counteracts TGF-beta 1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat. Med. 2003;9:964–968. doi: 10.1038/nm888. [DOI] [PubMed] [Google Scholar]

Articles from International Journal of Experimental Pathology are provided here courtesy of Wiley

RESOURCES