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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

Glomerular sclerosis in db/db–BMT and db/db mice. Representative Masson’s trichrome-stained glomeruli showing similar glomerular sclerotic lesions. Magnification ×100
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Fig1: Glomerular sclerosis in db/db–BMT and db/db mice. Representative Masson’s trichrome-stained glomeruli showing similar glomerular sclerotic lesions. Magnification ×100

Mentions: As we performed the experiments in EGFP+ chimeric mice, we first investigated whether BMT modified diabetic nephropathy in db/db mice. As shown in Table 1 and Fig. 1, both diabetic groups (db/db and db/db–BMT) were significantly different from the non-diabetic db/− group for body weight and albuminuria, as well as hyperglycaemia and glomerulosclerosis. There were no major differences between db/db and db/db–BMT. However, body weight was lower in the db/db–BMT mice compared with the db/db group, as would be expected as irradiation is usually associated with loss of body weight [22].Table 1


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)

Glomerular sclerosis in db/db–BMT and db/db mice. Representative Masson’s trichrome-stained glomeruli showing similar glomerular sclerotic lesions. Magnification ×100
© Copyright Policy
Related In: Results  -  Collection

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

Fig1: Glomerular sclerosis in db/db–BMT and db/db mice. Representative Masson’s trichrome-stained glomeruli showing similar glomerular sclerotic lesions. Magnification ×100
Mentions: As we performed the experiments in EGFP+ chimeric mice, we first investigated whether BMT modified diabetic nephropathy in db/db mice. As shown in Table 1 and Fig. 1, both diabetic groups (db/db and db/db–BMT) were significantly different from the non-diabetic db/− group for body weight and albuminuria, as well as hyperglycaemia and glomerulosclerosis. There were no major differences between db/db and db/db–BMT. However, body weight was lower in the db/db–BMT mice compared with the db/db group, as would be expected as irradiation is usually associated with loss of body weight [22].Table 1

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