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

• Published in: Diabetologia Vol. 55; no. 7; pp. 2059 - 2068
• Main Authors: Flaquer, M., Franquesa, M., Vidal, A., Bolaños, N., Torras, J., Lloberas, N., Herrero-Fresneda, I., Grinyó, J. M., Cruzado, J. M.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.07.2012; Springer; Springer Nature B.V
• Subjects: Animals; Associated diseases and complications; Biological and medical sciences; Bone marrow; Bowman's capsule; Connective tissue; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - therapy; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - therapy; Diabetic nephropathy; Disease Models, Animal; Disease Progression; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Epithelial cells; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Gene therapy; Genetic Therapy - methods; Granulocytes; Green fluorescent protein; Growth factors; Hepatocyte growth factor; Hepatocyte Growth Factor - genetics; Hepatocyte Growth Factor - therapeutic use; Hepatocytes - metabolism; HGF gene; Human Physiology; Internal Medicine; Kidney; Kidney diseases; Kidney Diseases - metabolism; Kidney Diseases - therapy; Kidneys; Laboratory animals; Liver; Macrophages; Macrophages - metabolism; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Transgenic; Monocytes; Nephrology; Nephrology. Urinary tract diseases; Nephropathy; Proteins; Regeneration; Stem cell transplantation; Stem cells; Urinary system involvement in other diseases. Miscellaneous; United States > US; Madrid Spain; Spain; Bone marrow stem cells; Diabetic nephropathy; gene therapy; Macrophages; Renal repair; Endocrinopathy; Kidney disease; Animal model; Urinary system disease; Hepatocyte growth factor; Stem cell; Diabetes mellitus; Rodentia; HGF gene therapy; Kidney; Concomitant disease; Vertebrata; Mammalia; Urinary system; Mouse; Animal; Bone marrow; Repair; Gene therapy; Macrophage
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-012-2535-z

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-marow-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.