Hepatocyte Growth Factor Gene Therapy Slows Down the Progression of Diabetic Nephropathy in &lt;i&gt;db/db&lt;/i&gt; Mice

Kagawa, Tomoyo; Takemura, Genzou; Kosai, Ken‐ichiro; Murata, Ichijiro; Ohno, Takamasa; Takahashi, Tomoyuki; Esaki, Masayasu; Maruyama, Rumi; Fujiwara, Takako; Ohashi, Hiroshige; Fujiwara, Hisayoshi

doi:10.1159/000090071

Cited by 27 publications

(21 citation statements)

References 63 publications

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“…In addition, HO-1 is upregulated in MSCtreated animals. HO-1 is an enzyme that converts heme into carbon monoxide, iron, and biliverdin (which is later converted into bilirubin) [58,59]. It is known that HO-1 has an important protective role in many aspects of normal physiology and pathological states [58,60].…”

Section: Discussionmentioning

confidence: 99%

“…HO-1 is an enzyme that converts heme into carbon monoxide, iron, and biliverdin (which is later converted into bilirubin) [58,59]. It is known that HO-1 has an important protective role in many aspects of normal physiology and pathological states [58,60]. Moreover, HO-1 deficiency is associated with increased fibrosis, tubular TGFb1 expression, inflammation, and enhanced EMT in obstructive kidney disease [61,62].…”

Section: Discussionmentioning

confidence: 99%

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Mesenchymal Stem Cells Attenuate Renal Fibrosis Through Immune Modulation and Remodeling Properties in a Rat Remnant Kidney Model

et al. 2009

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Mesenchymal stem cells (MSCs) have regenerative properties in acute kidney injury, but their role in chronic kidney diseases is still unknown. More specifically, it is not known whether MSCs halt fibrosis. The purpose of this work was to investigate the role of MSCs in fibrogenesis using a model of chronic renal failure. MSCs were obtained from the tibias and femurs of male Wistar-EPM rats. Female Wistar rats were subjected to the remnant model, and 2|3|10 5 MSCs were intravenously administrated to each rat every other week for 8 weeks or only once and followed for 12 weeks. SRY gene expression was observed in female rats treated with male MSCs, and immune localization of CD73 1 CD90 1 cells at 8 weeks was also assessed. Serum and urine analyses showed an amelioration of functional parameters in MSC-treated animals at 8 weeks, but not at 12 weeks. Masson's trichrome and Sirius red staining demonstrated reduced levels of fibrosis in MSC-treated animals. These results were corroborated by reduced vimentin, type I collagen, transforming growth factor b, fibroblast specific protein 1 (FSP-1), monocyte chemoattractant protein 1, and Smad3 mRNA expression and a smooth muscle actin and FSP-1 protein expression. Renal interleukin (IL)-6 and tumor necrosis factor a mRNA expression levels were significantly decreased after MSC treatment, whereas IL-4 and IL-10 expression levels were increased. All serum cytokine expression levels were decreased in MSC-treated animals. Taken together, these results suggested that MSC therapy can indeed modulate the inflammatory response that follows the initial phase of a chronic renal injury. The immunosuppressive and remodeling properties of MSCs may be involved in the decreased fibrosis in the kidney.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cells Attenuate Renal Fibrosis Through Immune Modulation and Remodeling Properties in a Rat Remnant Kidney Model

et al. 2009

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“…To allow the persistent expression of HGF, the gene was transferred into muscle tissue using either electroporation (47,48), or ultrasound delivery (8), or adenoviral vectors (49). Other therapeutic approaches entailed the administration of recombinant HGF i.p.…”

Section: Discussionmentioning

confidence: 99%

The Therapeutic Potential of Hepatocyte Growth Factor to Sensitize Ovarian Cancer Cells to Cisplatin and Paclitaxel In vivo

Bardella

Dettori

Olivero

et al. 2007

Clinical Cancer Research

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Purpose: Advanced ovarian cancers are initially responsive to combinatorial chemotherapy with platinum drugs and taxanes but, in most cases, develop drug resistance.We recently showed that, in vitro, hepatocyte growth factor (HGF) enhances death of human ovarian cancer cell lines treated with cisplatin (CDDP) and paclitaxel. The present study addresses whether in vivo HGF makes ovarian carcinoma cells more responsive to these chemotherapeutics. Experimental Design: Using Lentiviral vectors carrying the HGF transgene, we transduced SK-OV-3 and NIH:OVCAR-3 ovarian carcinoma cell lines to obtain stable autocrine and paracrine HGF receptor activation. In vitro, we assayed growth, motility, invasiveness, and the response to CDDP and paclitaxel of the HGF-secreting bulk unselected cell populations. In vivo, we tested the cytotoxic effects of the drugs versus s.c. tumors formed by the wild-type and HGF-secreting cells in immunocompromised mice. Tumor-bearing mice were treated with CDDP (i.p.) and paclitaxel (i.v.), combined in different schedules and doses. Results: In vitro, HGF-secreting cells did not show altered proliferation rates and survival but were strongly sensitized to the death triggered by CDDP and paclitaxel, alone or in combination. In vivo, we found a therapeutic window in which autocrine/paracrine HGF made tumors sensitive to low doses of the drugs, which were ineffective on their own. Conclusions:These data provide the proof-of-concept that in vivo gene therapy with HGF might be competent in sensitizing ovarian cancer cells to conventional chemotherapy.

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“…On the other hand, hepatocyte growth factor (HGF), originally identified and cloned as a mitogen for mature hepatocytes, exhibits potent renotropic properties and renoprotective role though the c-met receptor tyrosine kinase. A number of in vivo studies have demonstrated that HGF has potential therapeutic effect on diabetic nephropathy by suppressing ECM overproduction, but the relevant mechanism is little known [4,5,6,7]. Recent studies showed that HGF could retard oxidative stress-induced apoptosis as an antioxidant factor in many kinds of cells such as primary hepatocytes, human retinal-pigmented epithelial cells and human small airway epithelial cells[8,9,10].…”

Section: Introductionmentioning

confidence: 99%

HGF Protects Rat Mesangial Cells from High-Glucose-Mediated Oxidative Stress

Li¹,

Jiang²,

Lin³

et al. 2006

Am J Nephrol

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Background: Oxidative stress has been considered to be a common pathogenetic factor of diabetic nephropathy. Recent observations suggested that hepatocyte growth factor (HGF) was an antioxidant growth factor; thus, its renoprotective effects in diabetic nephropathy might be related to antioxidant mechanism. The aim of the present study was to evaluate whether HGF could prevent rat mesangial cells (RMC) from high-glucose-mediated oxidative stress and explore its relevant mechanism. Methods: RMC were cultured in 5.6 mM (NG) or 30 mM (HG) glucose in the absence or presence of HGF (20 ng/ml) and c-met inhibitor SU11274 (5 µM) for 24 h. Results: c-met expression in HG was markedly increased. Enhanced oxidative stress was observed in HG as evidenced by elevated reactive oxygen species and malondialdehyde levels and decreased glutathione level, which was markedly attenuated by HGF. HGF also inhibited HG-induced p22^phox and aldose reductase upregulation and prevented HG-reduced glutamate-cysteine ligase catalytic subunit (GCLC) expression through inhibiting USF binding to negative regulatory region of GCLC promoter. Reduced glucose-6-phosphate dehydrogenase activity and expression in RMC by HG was rescued by HGF. Conclusion: HGF could function as an antioxidant factor and protect against HG-mediated oxidative stress by enhancing ROS scavenging and suppressing ROS production.

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Hepatocyte Growth Factor Gene Therapy Slows Down the Progression of Diabetic Nephropathy in <i>db/db</i> Mice

Cited by 27 publications

References 63 publications

Mesenchymal Stem Cells Attenuate Renal Fibrosis Through Immune Modulation and Remodeling Properties in a Rat Remnant Kidney Model

Mesenchymal Stem Cells Attenuate Renal Fibrosis Through Immune Modulation and Remodeling Properties in a Rat Remnant Kidney Model

The Therapeutic Potential of Hepatocyte Growth Factor to Sensitize Ovarian Cancer Cells to Cisplatin and Paclitaxel In vivo

HGF Protects Rat Mesangial Cells from High-Glucose-Mediated Oxidative Stress

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