Interstitial fibrosis in mice with overload proteinuria: Deficiency of TIMP-1 is not protective

Eddy, Allison A.; Kim, Heung Soo; López-Guisa, Jesús M.; Oda, Takashi; Soloway, Paul D.; McCulloch, Lori; Liu, Elaine; Wing, Diane

doi:10.1046/j.1523-1755.2000.00208.x

Cited by 111 publications

(99 citation statements)

References 33 publications

(7 reference statements)

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“…Of note, decreased TIMP-3 expression has been associated with transition from an epithelial to fibroblast-like cell phenotype (40), suggesting that increased TIMP-3 expression after HGF might actually be beneficial, tending to block transdifferentiation. In contrast, TIMP-1 deficiency does not prevent renal injury in mice (33,46), and HGF was not associated with decrements in TIMP-1 expression in our rats.…”

Section: Discussioncontrasting

confidence: 69%

Hepatocyte Growth Factor Modulates Matrix Metalloproteinases and Plasminogen Activator/Plasmin Proteolytic Pathways in Progressive Renal Interstitial Fibrosis

Gong

Rifai²,

Tolbert³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Evidence suggests that hepatocyte growth factor (HGF) ameliorates renal fibrosis in animal models of chronic renal disease by promoting extracellular matrix catabolism. This study examined the molecular mechanisms of HGF-induced alterations in matrix degradation both in vitro and in vivo. In vitro, HGF increased the collagen catabolizing activity of human proximal tubular epithelial cells (HKC) that were treated with TGF-␤1. Increased collagen catabolism was associated with enhanced activity of both matrix metalloproteinases (MMP) and plasminogen activators (PA)/plasmin proteolytic pathways. HGF abrogated TGF-␤1-induced production of the profibrotic tissue inhibitor of metalloproteinase-2 (TIMP-2) and plasminogen activator inhibitor-1 (PAI-1). In addition, HGF induced the production of MMP-9. In vivo, continuous infusion of HGF in the rat remnant kidney model ameliorated renal fibrosis and tubulointerstitial collagen deposition. This was associated with increased tubular expression of MMP-9, enhanced in situ gelatinolytic activity, partially restored plasmin activity and decreased expression of TIMP-2 and PAI-1 in tubular cells, and upregulation of renal TIMP-3 expression. Conversely, blocking of endogenous HGF by an anti-HGF neutralizing antibody increased renal fibrosis and interstitial collagen. This was accompanied by decreased tubular expression of MMP-9, less in situ proteolytic activity, and elevated expression of TIMP-2 and PAI-1 in tubular cells. Collectively, these findings demonstrate that HGF ameliorates renal fibrosis by enhancing extracellular matrix catabolism via both MMP and the PA/plasmin proteolytic pathways.

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Section: Discussioncontrasting

confidence: 69%

Hepatocyte Growth Factor Modulates Matrix Metalloproteinases and Plasminogen Activator/Plasmin Proteolytic Pathways in Progressive Renal Interstitial Fibrosis

Gong

Rifai²,

Tolbert³

et al. 2003

Journal of the American Society of Nephrology

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“…In support of this hypothesis, a mouse that overexpresses human TIMP-1 was shown to develop more severe liver fibrosis when exposed to CCl 4 (39); however, other recent studies in addition to our work question the paradigm that fibrosis is prevented by MMP activity and promoted by TIMP (49,67). Indeed, the use of a synthetic MMP inhibitor batimastat was recently shown to decrease fibrosis in a bleomycin-induced pulmonary fibrosis model (67).…”

Section: Discussionsupporting

confidence: 66%

“…It is possible, however, that TIMP-1 and/or TIMP-2 are important regulators of fibrosis in other tissues or in other fibrotic disorders. Nevertheless, the fact that development of renal interstitial fibrosis was also unaffected by TIMP-1 deficiency suggests these findings may be more globally applicable (49). It is also important to mention that other ECM-regulating genes, such as ␣ 1 -macroglobulin or plasminogen activator inhibitor 1, could be compensating for the absence of TIMP-1 and TIMP-2, which may provide an alternative explanation for our findings.…”

Section: Discussionmentioning

confidence: 57%

Regulation of Hepatic Fibrosis and Extracellular Matrix Genes by the Th Response: New Insight into the Role of Tissue Inhibitors of Matrix Metalloproteinases

Vaillant

Chiaramonte

Cheever

et al. 2001

The Journal of Immunology

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117

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Hepatic fibrosis is the hallmark of Schistosoma mansoni infection and often results in portal hypertension and bleeding from esophageal varices. The fibrotic process is highly dependent on type 2 cytokines, yet their role in the regulation of extracellular matrix remodeling genes remains largely unknown. Here, we examined the expression of matrix metalloproteases (MMP) -2, -3, -9, -12, and -13 and their inhibitors, tissue inhibitor of metalloproteases (TIMP) -1, -2, and -3, in the livers of infected mice and correlated their expression profiles with fibrosis and type 2 cytokine production. Expression of MMP-2, -3, -9, -12, and -13 and of TIMP-1 and -2 mRNA rapidly increased at the onset of egg laying in infected mice, while TIMP-3 was unchanged. Because TIMP are presumed to be important regulators of the extracellular matrix, and their expression correlated with the development of fibrosis, we studied their role in fibrogenesis by infecting TIMP-1- and TIMP-2-deficient mice. Strikingly, our data revealed no role for TIMP-1 or -2 in the fibrotic pathology induced by S. mansoni eggs. Because of these findings, we infected IL-10/IFN-γ-deficient mice that develop an exaggerated fibrotic response to determine whether changes in type 2 cytokine dominance influence the pattern of MMP and TIMP expression. Fibrosis and type 2 cytokine production correlated with increased MMP-2/MMP-9 vs TIMP-1/TIMP-2 expression. These data, in addition to our knockout studies, demonstrate that TIMP-1/TIMP-2 play no essential role in fibrogenesis in schistosomiasis. Indeed, our findings suggest that inhibiting profibrotic cytokines or specific MMP may be a more effective strategy to ameliorate fibrotic pathology.

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“…Uninephrectomy was performed 5 d before starting BSA. 48,49 Low endotoxin BSA (Sigma A-9430, St. Louis, MO) was given 5 d weekly intraperitoneally (days 1 through 5) at the dosage of 15 mg/g body wt for 4 wk. Control WT and C3-deficient mice received the same volume of saline.…”

Section: Murine Model Of Protein Overload Proteinuriamentioning

confidence: 99%

Complement-Mediated Dysfunction of Glomerular Filtration Barrier Accelerates Progressive Renal Injury

Abbate

Zoja

Corna

et al. 2008

Journal of the American Society of Nephrology

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Intrarenal complement activation leads to chronic tubulointerstitial injury in animal models of proteinuric nephropathies, making this process a potential target for therapy. This study investigated whether a C3-mediated pathway promotes renal injury in the protein overload model and whether the abnormal exposure of proximal tubular cells to filtered complement could trigger the resulting inflammatory response. Mice with C3 deficiency were protected to a significant degree against the protein overload-induced interstitial inflammatory response and tissue damage, and they had less severe podocyte injury and less proteinuria. When the same injury was induced in wild-type (WT) mice, antiproteinuric treatment with the angiotensin-converting enzyme inhibitor lisinopril reduced the amount of plasma protein filtered, decreased the accumulation of C3 by proximal tubular cells, and protected against interstitial inflammation and damage. For determination of the injurious role of plasma-derived C3, as opposed to tubular cell-derived C3, C3-deficient kidneys were transplanted into WT mice. Protein overload led to the development of glomerular injury, accumulation of C3 in podocytes and proximal tubules, and tubulointerstitial changes. Conversely, when WT kidneys were transplanted into C3-deficient mice, protein overload led to a more mild disease and abnormal C3 deposition was not observed. These data suggest that the presence of C3 increases the glomerular filtration barrier's susceptibility to injury, ultrafiltered C3 contributes more to tubulointerstitial damage induced by protein overload than locally synthesized C3, and local C3 synthesis is irrelevant to the development of proteinuria. It is speculated that therapies targeting complement combined with interventions to minimize proteinuria would more effectively prevent the progression of renal disease.

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Interstitial fibrosis in mice with overload proteinuria: Deficiency of TIMP-1 is not protective

Cited by 111 publications

References 33 publications

Hepatocyte Growth Factor Modulates Matrix Metalloproteinases and Plasminogen Activator/Plasmin Proteolytic Pathways in Progressive Renal Interstitial Fibrosis

Hepatocyte Growth Factor Modulates Matrix Metalloproteinases and Plasminogen Activator/Plasmin Proteolytic Pathways in Progressive Renal Interstitial Fibrosis

Regulation of Hepatic Fibrosis and Extracellular Matrix Genes by the Th Response: New Insight into the Role of Tissue Inhibitors of Matrix Metalloproteinases

Complement-Mediated Dysfunction of Glomerular Filtration Barrier Accelerates Progressive Renal Injury

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