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Hepatocyte growth factor gene therapy enhances infiltration of macrophages and may induce kidney repair in db/db mice as a model of diabetes.

Flaquer M, Franquesa M, Vidal A, Bolaños N, Torras J, Lloberas N, Herrero-Fresneda I, Grinyó JM, Cruzado JM - Diabetologia (2012)

Bottom Line: The aim of this study was to test whether bone-marrow-derived cells are also involved in this HGF-induced reparative process.We have created chimeric db/db mice as a model of diabetes that produce enhanced green fluorescent protein (EGFP) in bone marrow cells.These cells are mainly monocyte-derived macrophages, which may contribute to the renal tissue repair and regeneration consistently observed in our model.

View Article: PubMed Central - PubMed

Affiliation: Nephrology Laboratory, Departament de Ciències Clíniques, IDIBELL, University of Barcelona, Bellvitge Hospital, Barcelona, Spain.

ABSTRACT

Aims/hypothesis: We previously demonstrated hepatocyte growth factor (HGF) gene therapy was able to induce regression of glomerulosclerosis in diabetic nephropathy through local reparative mechanisms. The aim of this study was to test whether bone-marrow-derived cells are also involved in this HGF-induced reparative process.

Methods: We have created chimeric db/db mice as a model of diabetes that produce enhanced green fluorescent protein (EGFP) in bone marrow cells. We performed treatment with HGF gene therapy either alone or in combination with granulocyte-colony stimulating factor, in order to induce mobilisation of haematopoietic stem cells in these diabetic and chimeric animals.

Results: We find HGF gene therapy enhances renal expression of stromal-cell-derived factor-1 and is subsequently associated with an increased number of bone-marrow-derived cells getting into the injured kidneys. These cells are mainly monocyte-derived macrophages, which may contribute to the renal tissue repair and regeneration consistently observed in our model. Finally, HGF gene therapy is associated with the presence of a small number of Bowman's capsule parietal epithelial cells producing EGFP, suggesting they are fused with bone-marrow-derived cells and are contributing to podocyte repopulation.

Conclusions/interpretation: Altogether, our findings provide new evidence about the therapeutic role of HGF and open new opportunities for inducing renal regeneration in diabetic nephropathy.

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Related in: MedlinePlus

HGF is associated with some parietal glomerular epithelial cells expressing EGFP and higher podocyte number. a Only mice receiving HGF gene therapy show glomerular parietal epithelial cells that express EGFP. Arrows in merged column are pointing at cells co-expressing claudin-I (red) and EGFP (green). b Amplified parietal epithelial cells expressing EGFP. Nuclear podocyte staining with WT-1 (in red) in HGF-treated (c) and HGF-non-treated mice (d). Nuclei are stained in blue with DRAQ5. Pink colour is the result of merged red (WT-1) and blue (DRAQ5). e Histogram showing the percentage of podocytes in HGF-treated and HGF-non-treated (‘non-treated’) animals (*p = 0.002, Student’s t test)
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Fig8: HGF is associated with some parietal glomerular epithelial cells expressing EGFP and higher podocyte number. a Only mice receiving HGF gene therapy show glomerular parietal epithelial cells that express EGFP. Arrows in merged column are pointing at cells co-expressing claudin-I (red) and EGFP (green). b Amplified parietal epithelial cells expressing EGFP. Nuclear podocyte staining with WT-1 (in red) in HGF-treated (c) and HGF-non-treated mice (d). Nuclei are stained in blue with DRAQ5. Pink colour is the result of merged red (WT-1) and blue (DRAQ5). e Histogram showing the percentage of podocytes in HGF-treated and HGF-non-treated (‘non-treated’) animals (*p = 0.002, Student’s t test)

Mentions: There was no co-expression of mesangial, endothelial and podocyte markers. Nevertheless, we found a small number (fewer than 0.5%) of Bowman’s capsule parietal epithelial cells (PECs) that were also EGFP+. Interestingly, this only happened in mice that received HGF gene therapy either alone or in combination with G-CSF (Fig. 8a, b). Accordingly, we found the percentage of podocytes was well preserved in HGF-treated compared with non-treated diabetic animals (Fig. 8c–e).Fig. 8


Hepatocyte growth factor gene therapy enhances infiltration of macrophages and may induce kidney repair in db/db mice as a model of diabetes.

Flaquer M, Franquesa M, Vidal A, Bolaños N, Torras J, Lloberas N, Herrero-Fresneda I, Grinyó JM, Cruzado JM - Diabetologia (2012)

HGF is associated with some parietal glomerular epithelial cells expressing EGFP and higher podocyte number. a Only mice receiving HGF gene therapy show glomerular parietal epithelial cells that express EGFP. Arrows in merged column are pointing at cells co-expressing claudin-I (red) and EGFP (green). b Amplified parietal epithelial cells expressing EGFP. Nuclear podocyte staining with WT-1 (in red) in HGF-treated (c) and HGF-non-treated mice (d). Nuclei are stained in blue with DRAQ5. Pink colour is the result of merged red (WT-1) and blue (DRAQ5). e Histogram showing the percentage of podocytes in HGF-treated and HGF-non-treated (‘non-treated’) animals (*p = 0.002, Student’s t test)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369134&req=5

Fig8: HGF is associated with some parietal glomerular epithelial cells expressing EGFP and higher podocyte number. a Only mice receiving HGF gene therapy show glomerular parietal epithelial cells that express EGFP. Arrows in merged column are pointing at cells co-expressing claudin-I (red) and EGFP (green). b Amplified parietal epithelial cells expressing EGFP. Nuclear podocyte staining with WT-1 (in red) in HGF-treated (c) and HGF-non-treated mice (d). Nuclei are stained in blue with DRAQ5. Pink colour is the result of merged red (WT-1) and blue (DRAQ5). e Histogram showing the percentage of podocytes in HGF-treated and HGF-non-treated (‘non-treated’) animals (*p = 0.002, Student’s t test)
Mentions: There was no co-expression of mesangial, endothelial and podocyte markers. Nevertheless, we found a small number (fewer than 0.5%) of Bowman’s capsule parietal epithelial cells (PECs) that were also EGFP+. Interestingly, this only happened in mice that received HGF gene therapy either alone or in combination with G-CSF (Fig. 8a, b). Accordingly, we found the percentage of podocytes was well preserved in HGF-treated compared with non-treated diabetic animals (Fig. 8c–e).Fig. 8

Bottom Line: The aim of this study was to test whether bone-marrow-derived cells are also involved in this HGF-induced reparative process.We have created chimeric db/db mice as a model of diabetes that produce enhanced green fluorescent protein (EGFP) in bone marrow cells.These cells are mainly monocyte-derived macrophages, which may contribute to the renal tissue repair and regeneration consistently observed in our model.

View Article: PubMed Central - PubMed

Affiliation: Nephrology Laboratory, Departament de Ciències Clíniques, IDIBELL, University of Barcelona, Bellvitge Hospital, Barcelona, Spain.

ABSTRACT

Aims/hypothesis: We previously demonstrated hepatocyte growth factor (HGF) gene therapy was able to induce regression of glomerulosclerosis in diabetic nephropathy through local reparative mechanisms. The aim of this study was to test whether bone-marrow-derived cells are also involved in this HGF-induced reparative process.

Methods: We have created chimeric db/db mice as a model of diabetes that produce enhanced green fluorescent protein (EGFP) in bone marrow cells. We performed treatment with HGF gene therapy either alone or in combination with granulocyte-colony stimulating factor, in order to induce mobilisation of haematopoietic stem cells in these diabetic and chimeric animals.

Results: We find HGF gene therapy enhances renal expression of stromal-cell-derived factor-1 and is subsequently associated with an increased number of bone-marrow-derived cells getting into the injured kidneys. These cells are mainly monocyte-derived macrophages, which may contribute to the renal tissue repair and regeneration consistently observed in our model. Finally, HGF gene therapy is associated with the presence of a small number of Bowman's capsule parietal epithelial cells producing EGFP, suggesting they are fused with bone-marrow-derived cells and are contributing to podocyte repopulation.

Conclusions/interpretation: Altogether, our findings provide new evidence about the therapeutic role of HGF and open new opportunities for inducing renal regeneration in diabetic nephropathy.

Show MeSH
Related in: MedlinePlus