Tubulointerstitial damage and progression of renal failure
2005; Elsevier BV; Volume: 68; Linguagem: Inglês
10.1111/j.1523-1755.2005.09915.x
ISSN1523-1755
AutoresBernardo Rodríguez‐Iturbe, Richard R. Johnson, Jaime Herrera-Acosta,
Tópico(s)Liver Disease and Transplantation
ResumoTubulointerstitial damage and progression of renal failure. The present work reviews the mechanisms and close association between glomerular and tubular damage and its relationship to renal functional impairment. In addition, we present an overview of the pathways involved in the progression of tubulointerstitial fibrosis and a brief summary of the treatments used to retard the progression to end-stage renal failure. Tubulointerstitial damage and progression of renal failure. The present work reviews the mechanisms and close association between glomerular and tubular damage and its relationship to renal functional impairment. In addition, we present an overview of the pathways involved in the progression of tubulointerstitial fibrosis and a brief summary of the treatments used to retard the progression to end-stage renal failure. This article will review briefly three aspects of the role of tubulointerstitial damage in the progression of renal failure: (1) the relationship between tubulointerstitial damage and deterioration of renal function; (2) the progression of tubulointerstitial fibrosis; and (3) therapeutic approaches to retard progression of renal disease. The first report showing a correlation between tubulointerstitial damage and impairment of renal function was made more than three decades ago in studies of patients with persistent glomerulonephritis1Risdon R.A. Sloper J.C. De Wardener H.E. Relationship between renal function and histological changes found in renal biopsy specimens from patients with persistent glomerular nephritis.Lancet. 1968; 2: 363-366Google Scholar. These observations have been amply confirmed in subsequent years2Schainuck L.I. Stricker G.E. Cutler R.E. Benditt E.P. Structural-functional correlations in renal disease. II. The correlations.Human Pathol. 1970; 1: 631-641Google Scholar, 3Mackensen-Haen S. Bader R. Grund K.E. Bohle A. Correlations between renal cortical interstitial fibrosis, atrophy of the proximal tubules and impairment of the glomerular filtration rate.Clin Nephrol. 1981; 15: 167-171Google Scholar, 4Nath K.A. Tubulointerstitial changes as a major determinant in the progression of renal damage.Am J Kidney Dis. 1992; 20: 1-17Google Scholar. In specific diseases, such as diabetes, the increment in interstitial fibrosis over time is directly correlated with the decrease in creatinine clearance5Gilbert R.E. Cooper M.E. The tubulointerstitium in progressive diabetic kidney disease: More than an aftermath of glomerular injury?.Kidney Int. 1999; 56: 1627-1637Google Scholar. In contrast, the degree of glomerular injury does not correlate as well with renal outcomes1Risdon R.A. Sloper J.C. De Wardener H.E. Relationship between renal function and histological changes found in renal biopsy specimens from patients with persistent glomerular nephritis.Lancet. 1968; 2: 363-366Google Scholar, 2Schainuck L.I. Stricker G.E. Cutler R.E. Benditt E.P. Structural-functional correlations in renal disease. II. The correlations.Human Pathol. 1970; 1: 631-641Google Scholar, 3Mackensen-Haen S. Bader R. Grund K.E. Bohle A. Correlations between renal cortical interstitial fibrosis, atrophy of the proximal tubules and impairment of the glomerular filtration rate.Clin Nephrol. 1981; 15: 167-171Google Scholar, 4Nath K.A. Tubulointerstitial changes as a major determinant in the progression of renal damage.Am J Kidney Dis. 1992; 20: 1-17Google Scholar, 5Gilbert R.E. Cooper M.E. The tubulointerstitium in progressive diabetic kidney disease: More than an aftermath of glomerular injury?.Kidney Int. 1999; 56: 1627-1637Google Scholar. This is likely because periglomerular fibrosis may lead to peritubular scarring with hindrance of flow into the proximal tubule. In this situation, the glomerulus may appear structurally normal but, in essence, is “atubular.” The demonstration that the number of atubular glomeruli far exceeds the number of glomeruli with global sclerosis in the renal ablation model6Gandhi M. Olson J.L. Meyer T.W. Contribution of tubular injury to loss of remnant kidney function.Kidney Int. 1998; 54: 1157-1165Google Scholar made evident that relatively preserved glomerular structure does not imply a functioning nephron, and provides a ready explanation for the superiority of using tubulointerstitial scores rather than glomerular scores in the prediction of renal outcome. Tubulointerstitial damage and reduction in glomerular filtration rate (GFR) are inextricably associated. Tubuloglomerular feedback would reduce GFR, if increased distal delivery results in proximal tubular injury with reduced sodium reabsorption. Glomerular damage, resulting in postglomerular ischemia, is associated with downstream hypoxia and unchecked oxidative stress, tubular injury, and eventual nephron loss that, in turn, impose hemodynamic stress in the remaining nephron units. Tubulointerstitial injury may be due to direct tubular damage (resulting from toxic, obstructive, or ischemic mechanisms) or may be a consequence of glomerular damage with the passage of cytokines and growth factors into the urine. Extensive studies by Kriz et al 7Kriz W. Hosser H. Hahnel B. et al.From segmental glomerulosclerosis to total nephron degeneration and interstitial fibrosis: A histopathological study in rat models and human glomerulopathies.Nephrol Dial Transpl. 1998; 13: 2781-2798Google Scholar , 8Kriz W. Lehir M. Pathways to nephron loss starting from glomerular diseases—Insights from animal models.Kidney Int. 2005; 67: 404-419Google Scholar have elucidated additional histopathologic pathways of tubulointerstitial injury induced by glomerular damage. Degenerative and inflammatory lesions cause cell bridges and fibrous adhesions between the glomerular tuft and Bowman's capsule, which cause a diversion of part of the glomerular filtrate toward the periglomerular areas. This misdirected urine, as well as the protein leakage in the tubular urine, causes interstitial inflammation and direct encroachment of the tubule, disconnection from the glomerulus, and functional nephron loss. Several factors play an important role in the progression of renal damage. Proteinuria may be a risk factor or a marker of disease severity, but has been proven to be a useful prognostic and therapeutic guide in the long-term management of chronic renal damage9Zandi-Nejad K. Eddy A.A. Glassock R.J. Brenner B.M. Why is proteinuria an ominous biomarker of progressive kidney disease?.Kidney Int. 2004: S76-S89Google Scholar. Inappropriate activation of the alternative pathway of complement at the apical membrane of tubular cells may also play a pathogenic role, likely mediated by the C5b-9 membrane attack complex10Morita Y. Nomura A. Yuzawa Y. et al.The role of complement in the pathogenesis of tubulointerstitial lesions in rat mesangial proliferative glomerulonephritis.J Am Soc Nephrol. 1997; 8: 1363-1372Google Scholar , 11Nangaku M. Pippin J. Couser W.G. Complement membrane attack complex (C5b-9) mediates interstitial disease in experimental nephritic syndrome.J Am Soc Nephrol. 1999; 10: 2323-2331Google Scholar. Oxidative stress is both a cause and consequence of interstitial inflammation. Tissue hypoxia resulting from angiotensin-induced vasoconstriction or structural disruption of peritubular capillaries is a final common pathway in the development of tubulointerstitial fibrosis. Hypoxia can activate fibroblasts12Norman J.T. Clark I.M. Garcia P.L. Hypoxia promotes fibrogenesis in human renal fibroblasts.Kidney Int. 2000; 58: 2351-2366Google Scholar, trigger epithelial mesenchymal transdifferentiation (EMT)13Manotham K. Tanaka T. Matsumoto M. et al.Transdifferentiation of cultured tubular cells induced by hypoxia.Kidney Int. 2004; 65: 871-880Google Scholar, and induce tubular cell apoptosis14Kahn S. Cleveland R.P. Koch C.J. Schelling J.R. Hypoxia induces renal tubular cell apoptosis in chronic renal disease.Lab Invest. 1999; 79: 1089-1099Google Scholar. Because chronic tubulointerstitial damage is characterized by an increase in extracellular matrix, the factors involved in the synthesis and degradation of metalloproteinases are of critical importance. These factors have been authoritatively reviewed15Eddy A.A. Molecular insights into renal interstitial fibrosis.J Am Soc Nephrol. 1996; 7: 2495-2508Google Scholar. There is wide recognition that infiltrating cells play a key role in the chronic renal damage of any etiology16Rodriguez-Iturbe B. Pons H. Herrera-Acosta J. Johnson R.J. The role of immunocompetent cells in non-immune renal diseases.Kidney Int. 2001; 59: 1626-1640Google Scholar. The principal cells involved in collagen deposition are fibroblasts, which may be resident, bone marrow–derived cells, and tubular epithelial cells transformed in myofibroblasts by a complex process of transdifferentiation in which renal tubular cells lose their epithelial phenotype and acquire mesenchymal characteristics (EMT)17Iwano M. Neilson E.G. Mechanisms of tubulointerstitial fibrosis.Curr Opin Nephrol Hypertens. 2004; 13: 279-284Google Scholar , 18Liu Y. Epithelial to mesenchymal transition in renal fibrogenesis: Pathologic significance, molecular mechanisms and therapeutic intervention.J Amer Soc Nephrol. 2004; 25: 1-12Google Scholar. Figure 1 shows an overview of the major steps involved in the development of tubulointerstitial fibrosis. After Strutz et al 19Strutz F. Okada H. Lo C.W. et al.Identification and characterization of a fibroblast marker: FSP1.J Cell Biol. 1995; 130: 393-405Google Scholar postulated that EMT could represent a mechanism for generating fibroblasts in the kidney, several investigators found de novo expression of alpha smooth muscle cell actin (αSMA) and actin filaments in tubular epithelial cells three weeks after renal ablation20Ng Y.Y. Huang T.P. Yang W.C. et al.Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats.Kidney Int. 1998; 54: 864-876Google Scholar. Afterwards, evidence of EMT was obtained in a variety of experimental models of chronic renal damage18Liu Y. Epithelial to mesenchymal transition in renal fibrogenesis: Pathologic significance, molecular mechanisms and therapeutic intervention.J Amer Soc Nephrol. 2004; 25: 1-12Google Scholar. The importance of this process was underlined by Yang et al 21Yang J. Shuktz R.W. Mars W.M. et al.Disruption of tissue-type plasminogen activator gene in mice reduces renal interstitial fibrosis in obstructive nephropathy.J Clin Invest. 2002; 110: 1525-1538Google Scholar, who showed that in the absence of this process, myofibroblast accumulation was reversed. As described by Liu18Liu Y. Epithelial to mesenchymal transition in renal fibrogenesis: Pathologic significance, molecular mechanisms and therapeutic intervention.J Amer Soc Nephrol. 2004; 25: 1-12Google Scholar, there are four key events in EMT: loss of adhesion properties, de novo expression of αSMA and actin reorganization, disruption of tubular basement membrane, and enhanced cell migration of cells in transition from epithelial to mesenchymal phenotype toward interstitial areas. The process of EMT is regulated by a variety of factors that promote (transforming growth factor-β[TGF-β], epithelial growth factor, interleukin 1, angiotensin II, connective tissue growth factor [CTGF], advanced glycation end products, matrix metalloproteinase-2, type I collagen) or inhibit (bone morphogenic protein-7, hepatocyte growth factor) cellular transdifferentiation. The intracellular pathways for EMT involve phosphorylation of Smad-2 and Smad-3 that forms a complex with Smad-4 and is translocated into the nucleus where it induces the transcription of TGF-β responsive genes. In addition, TGF-β activates other pathways, such as p38 MAPK and RhoA. Interestingly, the EMT process may be potentially reversible if chronic injury is suppressed18Liu Y. Epithelial to mesenchymal transition in renal fibrogenesis: Pathologic significance, molecular mechanisms and therapeutic intervention.J Amer Soc Nephrol. 2004; 25: 1-12Google Scholar. Finally, in addition to EMT, it is also likely that intrinsic fibroblasts themselves can alter their phenotype into myofibroblasts and thereby also contribute to the fibrotic process. Several treatments have been shown to halt or retard the progression of chronic renal disease in experimental animals and in humans. Some of these treatments have a variety of effects that combine to have a beneficial effect, whereas others are directed to modify specific steps in the pathway leading toward renal fibrosis Table 1 . Among the former, the suppression of the renin angiotensin system is currently the most widely used in clinical practice. It is now evident that the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor type 1 blocker (ARB) are not only the result of reducing glomerular hypertension, but are also due to suppression of the proinflammatory and vasoconstrictor actions of angiotensin II. A recent example of these multiple effects is given by the studies in the genetically hyperlipemic Imai rat strain22Rodriguez-Iturbe B. Sato T. Quiroz Y. Vaziri N.D. AT-1 receptor blockade prevents proteinuria, renal failure, hyperlipidemia and glomerulosclerosis in the Imai rat.Kidney Int. 2004; 66: 668-675Google Scholar and the suppression of angiotensinogen gene expression in unilateral ureteral obstruction23Shin G.-T. Kim W.H. Yim H. et al.Effects of suppressing intrarenal angiotensinogen on renal transforming growth factor B1 expression in acute ureteral obstruction.Kidney Int. 2005; 67: 897-980Google Scholar. Large, multicenter, randomized studies have shown the value of ACE inhibitors and ARBs in reducing proteinuria and delaying end-stage renal disease. Relatively novel therapeutic strategies presently under evaluation include the combined use of ACE and ARB24Wolf G. Ritz E. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: Pathophysiology and indications.Kidney Int. 2005; 67: 799-812Google Scholar and the use of very large doses of ACE inhibitors25Adamczak M. Gross M.L. Krtil J. et al.Reversal of glomerulosclerosis after high dose enalapril treatment in subtotally nephrectomized rats.J Am Soc Nephrol. 2003; 14: 2833-2842Google Scholar. Statins also belong to the group of therapies that have several beneficial effects, in addition to their lipid-lowering activity. Among them, the most recently demonstrated benefit is the blockade of TGF-β-dependent transcriptional activation of CTGF26Watts K. Spiteri M. Connective tissue growth factor expression and induction by transforming growth factor-β is abrogated by simvastatin via a Rho signaling mechanism.Am J Physiol Lung Cell Mol Physiol. 2004; 287: L1323-L3332Google Scholar. A number of studies have shown that the treatments directed to increase nitric oxide bioavailability are renoprotective27Zoja C. Benigni A. Camozzi D. et al.Combining lisinopril and L-arginine slows disease progression and reduces endothelin-1 in passive Heyman nephritis.Kidney Int. 2003; 64: 857-863Google Scholar, 28Reyes A.A. Purkerson M.L. Karl I. Klahr S. Dietary supplementation with L-arginine ameliorates the progression of renal disease in rats with subtotal nephrectomy.Am J Kidney Dis. 1992; 20: 168-176Google Scholar, 29Ashab I. Peer G. Blum M. et al.Oral administration of L-arginine and captopril in rats prevents chronic renal failure by nitric oxide production.Kidney Int. 1995; 47: 1515-1521Google Scholar. However, nitric oxide donors may exert cytotoxicity by facilitating the formation of peroxynitrite from the interaction of nitric oxide with superoxide30Rodriguez-Iturbe B. Vaziri N.D. Herrera-Acosta J. Johnson R.J. Oxidative stress, renal infiltration of immune cells and salt-sensitive hypertension: All for one and one for all.Am J Physiol Renal Physiol. 2004; 286: F606-F616Google Scholar, which can limit their potential benefit in the treatment of renal disease31Rangan G.K. Wang Y. Harris D.C. Pharmacologic modulators of nitric oxide exacerbate tubulointerstitial inflammation in proteinuric rats.J Am Soc Nephrol. 2001; 12: 1696-1705Google Scholar. Immunosuppressive agents such as mycophenolate mofetil (MMF) have been used to reduce the renal inflammatory infiltrate. We and others have shown that MMF ameliorates the progression of renal damage in the remnant kidney32Fujihara C.K. Malheiros D.M. Zatz R. Noronha I.D. Mycophenolate mofetil attenuates renal injury in the rat remnant kidney.Kidney Int. 1998; 54: 1510-1519Google Scholar, 33Romero F. Rodriguez-Iturbe B. 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The cellophane-wrapped (Page kidney) model, which is characterized by significant tubulointerstitial inflammation, is another model in which chronic tubulointerstitial inflammation and associated hypertension are significantly ameliorated by MMF treatment37Vanegas V. Ferrebuz A. Quiroz Y. Rodriguez-Iturbe B. Hypertension in Page (cellophane-wrapped) kidney is due to interstitial nephritis.Kidney Int. 2005; 68: 1161-1170Google Scholar. The beneficial effects of this drug are probably a combination of multiple mechanisms, because it not only inhibits proliferation of immune cells, but also blocks proliferation of smooth muscle cells, mesangial cells, and fibroblasts38Hauser I.A. Renders L. Radeke H.-H. et al.Mycophenolate mofetil inhibits rat and human mesangial cell proliferation by guanosine depletion.Nephrol Dial Transplant. 1999; 14: 58-63Google Scholar , 39Badid C. Vincent M. Mcgregor B. et al.Mycophenolate mofetil reduces myofibroblast infiltration and collagen III deposition in rat remnant kidney.Kidney Int. 2000; 58: 51-61Google Scholar. Rapamycin is another immunosuppressive drug that has proven to be of benefit in retarding the progression of kidney damage. Recent studies indicate that rapamycin reduced proliferation of tubular cells and inhibits cystogenesis in the Han:SPRD rat model of polycystic kidney disease40Tao Y. Kim J. Schrier R.W. Edelstein C.L. Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease.J Am Soc Nephrol. 2005; 16: 46-51Google Scholar. Pirfenidone has been found to reduce fibrosis in the renal ablation model, experimental ureteral obstruction, and cyclosporine nephropathy. The mechanism of inhibition of fibrosis by pirfenidone is incompletely elucidated; reduction in profibrotic gene expression, suppression of TGF-β or its effects, inhibition of tumor necrosis factor-α, and downregulation of platelet-derived growth factor expression have all been implicated41Negri A.L. Prevention of progressive fibrosis in chronic renal diseases: Antifibrotic agents.J Nephrol. 2004; 17: 496-503Google Scholar. Relaxin reduces collagen deposition likely because of stimulating ubiquitin-mediated degradation42Mcdonald G.A. Sarkar P. Rennke H. et al.Relaxin increases ubiquitin-dependent degradation of fibronectin in vitro and ameliorates renal fibrosis in vivo.Am J Physiol Renal Physiol. 2003; 285: F59-F67Google Scholar , 43Garber S.L. Mirochnik Y. Brecklin C.S. et al.Relaxin decreases renal interstitial fibrosis and slows progression of renal disease.Kidney Int. 2001; 59 (872): 876Google Scholar. Antagonists of monocyte chemotactic protein-1 and reduction of IκBα activity by gene transfer of the IκBα inhibitor have been shown to reduce macrophage infiltration and interstitial fibrosis in protein overload nephropathy44Shimizu H. Maruyama S. Yuzawa Y. et al.Anti-monocyte chemoattractant protein-1 gene therapy attenuates renal injury induced by protein-overload proteinuria.J Am Soc Nephrol. 2003; 14: 1496-1505Google Scholar , 45Takase O. Hirahashi J. Takayanagi A. et al.Gene transfer of truncated IκBα prevents tubulointerstitial injury.Kidney Int. 2003; 63: 501-513Google Scholar. Several recent studies suggest that selective and unselective endothelin-1 receptor antagonists46Wolf S.C. Brehm B.R. Gaschker P. et al.Protective effects of endothelin antagonists in chronic renal failure.Nephrol Dial Transplant. 1999; 14: S29-30Google Scholar, aldosterone antagonists47Arima S. Kohagura K. Xu H.L. et al.Non-genomic vascular action of aldosterone in glomerular microcirculation.J Am Soc Nephrol. 2003; 14: 2255-2263Google Scholar, and retinoids48Schaier M. Jocks T. Grone H.J. et al.Retinoid agonist isotretinoin ameliorate obstructive renal injury.J Urol. 2003; 170: 1398-1402Google Scholar also appear to be promising. Similarly, further investigations are required to expand a provocative recent investigation that has shown that 1,25-dihydroxy vitamin D protects podocyte integrity and prevents glomerulosclerosis and tubulointerstitial damage in the remnant kidney model49Khulmann A. Haas C.S. Gross M.L. et al.1,25-dihydroxyvitamin D decreases podocyte loss and podocyte hypertrophy in the subtotally nephrectomized rat.Am J Physiol Renal Physiol. 2004; 286: F526-F533Google Scholar. Improvement of tubulointerstitial hypoxia by the preservation of capillary endothelium and reversal of impaired angiogenesis is thought to play a role in the beneficial effects found within the administration of vascular endothelium growth factor in the remnant kidney model50Kang D.H. Hughes J. Mazzali M. et al.Impaired angiogenesis in the remnant kidney model. II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function.J Am Soc Nephrol. 2001; 12: 1448-1457Google Scholar. Erythropoietin may also improve renal disease in part via its ability to stimulate vascular endothelium growth factor and angiogenesis51Kang D.H. Park E.Y. Yu E.S. et al.Renoprotective effect of erythropoietin (EPO): Possibly via an amelioration of renal hypoxia with stimulation of angiogenesis in the kidney.Kidney Int. 2005; 67: 1683Google Scholar. There are also interventions in specific pathways leading to tubulointerstitial fibrosis Table 1. Hepatocyte growth factor prevents transcriptional activation of Smad promoters (inducing snoN repressors) and reduces CTGF response to TGF-β, resulting in inhibition of TGF-β signals and activating matrix degradation. Systemic injection of hepatocyte growth factor reduces fibrosis in the remnant kidney in rats52Liu Y. Rajur K. Tolbert E. Dworkin L.D. Endogenous hepatocyte growth factor ameliorates chronic renal injury by activating matrix degradation pathways.Kidney Int. 2000; 58: 2028-2043Google Scholar and in the mouse model of obstructive uropathy53Mizuno S. Matsumoto K. Wen J. Nakamura T. Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy.Kidney Int. 2001; 59: 1304-1314Google Scholar. Bone morphologic protein-7 reduces the nuclear translocation of the Smad 2/3/4 complex induced by TGF-β and has been found to reduce fibrosis in obstructive and diabetic nephropathies primarily by inhibiting TGF-β-mediated EMT54Zeisberg M. Hanai J. Sugimoto H. et al.BMP-7 counteracts TGF-β1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury.Nat Med. 2003; 9: 964-968Google Scholar , 55Wang S. Chen Q. Simon T.C. et al.Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy.Kidney Int. 2003; 63: 2037-2049Google Scholar. Rho-associated coiled-coil forming protein kinase (ROCK) inhibition has recently been found also to suppress key steps in the EMT, such as αSMA expression, cell migration, and interstitial fibrosis in obstructive uropathy56Nagatoya K. Moriyama T. Kawada N. et al.Y-27632 prevents tubulointerstitial fibrosis in mouse kidneys with unilateral ureteral obstruction.Kidney Int. 2002; 61: 1684-1695Google Scholar. The systemic administration of neutralizing antibodies that block TGF-α activity prevented renal fibrosis and renal insufficiency in the diabetic mice57Ziyadeh F.N. Hoffman B.B. Han D.C. et al.Long-term prevention of renal insufficiency, excess matrix expression and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-β antibody in db/db diabetic mice.Proc Natl Acad Sci USA. 2000; 97: 8015-8020Google Scholar. The administration of antisense oligonucleotide to reduce the expression of CTGF in the rat model of obstructive uropathy resulted in reduction of collagen deposition and myofibroblast accumulation58Yokoi H. Mukoyama M. Nagae T. et al.Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstitial fibrosis.J Am Soc Nephrol. 2004; 15: 1430-1440Google Scholar. Imatinib mesylate is an inhibitor of the abelson nonreceptor (c-abl) tyrosine kinase with the capacity to reduce fibroblast proliferation, which is currently used in the treatment of chronic myelogenous leukemia. Recent studies have shown that it is capable of reducing myofibroblast accumulation and collagen deposition in models of obstructive uropathy, thus showing that not only TGF-β-dependent pathways are important in the development of renal fibrosis59Wang S. Wilkes M.C. Leof E.B. Hirschberg R. Imatinib mesylate blocks a non-Smad TGF-β pathway and reduces renal fibrogenesis in vivo.FASEB J. 2005; 19: 1-11Google Scholar. In summary, there are currently effective treatments to retard the progression of chronic renal disease. Promising new therapies, targeted to suppress specific aspects of the pathways that lead to end-stage renal disease, are in the process of being evaluated for their capacity to prevent arrest and, hopefully, reverse tubulointerstitial fibrosis.Table 1Treatments used to retard progression of chronic renal failureInterventions that affect multiple systems involved in development of fibrosis Anti-angiotensin treatments (ACE inhibitors, ARB, combined ACE+ARB, suppression of intrarenal angiotensinogen) Statins Nitric oxide donors Mycophenolate mofetil COX II inhibitors Rapamycin Pirfenidone Relaxin MCP-1 inhibitors IκBα Endothelin receptor blockade Aldosterone antagonists Retinoids Erythropoietin Vitamin D VEGFInterventions in specific pathways leading to tubulointerstitial fibrosis HGF BMP-7 ROCK inhibitors (Y-27632) Anti-TGF-β neutralizing antibodies Antisense CTGF Imatinib mesylateAbbreviations are: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor type 1 blocker; COX, cytochrome c oxidase; MCP-1, monocyte chemotactic protein-1; VEGF, vascular endothelium growth factor; HGF, hepatocyte growth factor; BMP-7, bone morphogenic protein-7; TGF-β, transforming growth factor- β; CTGF, connective tissue growth factor. Open table in a new tab Abbreviations are: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor type 1 blocker; COX, cytochrome c oxidase; MCP-1, monocyte chemotactic protein-1; VEGF, vascular endothelium growth factor; HGF, hepatocyte growth factor; BMP-7, bone morphogenic protein-7; TGF-β, transforming growth factor- β; CTGF, connective tissue growth factor. Work in Dr. Rodriguez-Iturbe's lab is supported by grants from FONACYT, Venezuela, and Asociación de Amigos del Riñón, Maracaibo.
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