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

Gong, Rujun; Rifai, Abdalla; Tolbert, Evelyn; Centracchio, Jason; Dworkin, Lance D.

doi:10.1097/01.asn.0000098686.72971.db

Cited by 89 publications

(76 citation statements)

References 49 publications

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“…ECM is mainly degraded through two distinct pathways: the MMP degrading pathway and the PA/plasmin proteolytic axis. 40 In this study, inhibition of epimorphin by antibody prominently decreased the expression of MMP-2 and MMP-9 in UUO-R kidneys. This finding is supported by the effect of recombinant epimorphin on renal interstitial fibroblasts (NRK-49F cells) in vitro.…”

Section: Discussionmentioning

confidence: 92%

Involvement of epimorphin in the repair of experimental renal fibrosis in mice

Yamada¹,

Oda²,

Higashi³

et al. 2010

Laboratory Investigation

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Interaction between epithelial cells and mesenchymal cells is essential in normal organ morphogenesis and in tissue repair after injury. Epimorphin, a mesenchymal protein that regulates epithelial morphogenesis through epithelialmesenchymal interactions, has recently attracted attention as an important modulator of tissue repair. In this study we analyzed the role of epimorphin in renal fibrosis. We first found a progressive increase in epimorphin expression corresponding to the progression of renal fibrosis in mice with unilateral ureteral obstruction (UUO). To determine whether this expression has a role in the repair or progression of renal fibrosis, we analyzed a model of renal fibrosis repair, the UUO-release (UUO-R) model. Epimorphin expression was increased at 3 and 7 days after the UUO-R rather than on the day of release, but was decreased at 21 days after the release. Inhibition of endogenous epimorphin with antiepimorphin antibody (MC-1) significantly delayed the repair of fibrosis. When compared with normal-IgG-injected mice, MC-1-injected mice showed significantly decreased renal matrix metalloproteinase (MMP)-2 and MMP-9 expressions by western blotting and increased expression of TGF-b and collagen-I mRNA by real-time RT-PCR. Recombinant epimorphin induced prominent increases in MMP-2 and MMP-9 activities in the culture media of renal interstitial fibroblasts in vitro. These findings indicate that epimorphin has a pivotal role in the repair of renal fibrosis by modulating both extracellular matrix (ECM) degradation and its production.

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Section: Discussionmentioning

confidence: 92%

Involvement of epimorphin in the repair of experimental renal fibrosis in mice

Yamada¹,

Oda²,

Higashi³

et al. 2010

Laboratory Investigation

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“…In part, this may be related to HGF's activity of suppressing TGF- (258,287). Treatment with HGF suppressed, and blockade of HGF worsened, experimental renal fibrosis (287)(288)(289). Importantly, HGF administration synergized with angiotensin-II blockade in antagonizing renal fibrosis (290).…”

Section: Connective Tissue Growth Factormentioning

confidence: 99%

Renal Allograft Fibrosis: Biology and Therapeutic Targets

Floege

2015

American Journal of Transplantation

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“…For urine collection, rats were placed in metabolic cages for 24 h, urine volume measured, and urine protein was determined as described previously (27). Blood was obtained from the tail vein.…”

Section: Whole-animal Studiesmentioning

confidence: 99%

Long-Term, High-Dosage Candesartan Suppresses Inflammation and Injury in Chronic Kidney Disease

Chen¹,

Gong²,

Rifai

et al. 2007

Journal of the American Society of Nephrology

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Recent evidence suggests that higher-than-usual antihypertensive dosages of renin-angiotensin-aldosterone system blockers may provide additional protection from progression of chronic renal disease; however, there have been few long-term studies, and the underlying mechanisms remain uncertain. This study examined the effects of long-term (14 mo) administration of ultrahigh dosages of the angiotensin receptor blocker candesartan on the progression of renal injury in spontaneously hypertensive rats (SHR). Beginning 8 wk after birth, SHR underwent unilateral nephrectomy and were given vehicle (control), or candesartan at a standard 5 mg/kg per d (T5), high 25 mg/kg per d (T25), or ultrahigh 75 mg/kg per d dosage (T75). After 2 wk, BP was reduced in all treated groups; however, it was better controlled in the high-dosage groups (T25 and T75). Urinary protein was significantly reduced in T75 after 2 wk of treatment and was also declined in the other two treatment groups but only after 2 mo. Exogenous angiotensin II test showed that complete angiotensin receptor blockade was achieved only in the high-dosage groups. Renal inflammation and macrophage (ED-1) infiltration were significantly ameliorated in both T25 and T75 but not in T5 rats. This was associated with the changes of tubular expression of monocyte chemoattractant protein-1, RANTES (regulated upon expression normal T cell expressed and secreted), and the phosphorylated NF-B, a marker for activation. Suppression of ED-1, monocyte chemoattractant protein-1, and RANTES expression and NF-B activation were greater in T75 as compared with T25. These findings suggest that candesartan has dosage-dependent, anti-inflammatory effects that are mediated by suppression of NF-B activation and chemokine expression. Renal protection with high-dosage therapy may depend on these nonhemodynamic effects.

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

Cited by 89 publications

References 49 publications

Involvement of epimorphin in the repair of experimental renal fibrosis in mice

Involvement of epimorphin in the repair of experimental renal fibrosis in mice

Renal Allograft Fibrosis: Biology and Therapeutic Targets

Long-Term, High-Dosage Candesartan Suppresses Inflammation and Injury in Chronic Kidney Disease

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