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Diabetes 53:1119-1127, 2004
© 2004 by the American Diabetes Association, Inc.

Regression of Advanced Diabetic Nephropathy by Hepatocyte Growth Factor Gene Therapy in Rats

Josep M. Cruzado1, Núria Lloberas2, Joan Torras1, Marta Riera2, Cristina Fillat3, Immaculada Herrero-Fresneda2, Josep M. Aran4, Gabriela Alperovich1, August Vidal5, and Josep M. Grinyó1

1 Nephrology Service, Medicine Department, Hospital Universitari Bellvitge, University of Barcelona, Catalonia, Spain
2 Laboratory of Nephrology, Medicine Department, Hospital Universitari Bellvitge, University of Barcelona, Catalonia, Spain
3 Genes and Disease Program, Centre de Regulació Genòmica (CRG), Barcelona, Catalonia, Spain
4 Medical and Molecular Genetic Center, Institut de Recerca Oncològica (IRO), Catalonia, Spain
5 Pathology Department, Hospital Universitari Bellvitge, Catalonia, Spain

Diabetic nephropathy is the main cause of end-stage renal disease requiring dialysis in developed countries. In this study, we demonstrated the therapeutic effect of hepatocyte growth factor (HGF) on advanced rather than early diabetic nephropathy using a rat model of streptozotocin-induced diabetes. Early diabetic nephropathy (16 weeks after induction of diabetes) was characterized by albuminuria, hyperfiltration, and glomerular hypertrophy, whereas advanced diabetic nephropathy showed prominent transforming growth factor (TGF)-ß1 upregulation, mesangial expansion, and glomerulosclerosis. An SP1017-formulated human HGF (hHGF) plasmid was administered by intramuscular injection combined with electroporation over a 30-day follow-up in rats with early and advanced diabetic nephropathy. hHGF gene therapy upregulated endogenous rat HGF in the diabetic kidney (rat HGF by RT-PCR was threefold higher than in diabetic rats without therapy). hHGF gene therapy did not improve functional or morphologic abnormalities in early diabetic nephropathy. hHGF gene therapy reduced albuminuria and induced strong regression of mesangial expansion and glomerulosclerosis in advanced diabetic nephropathy. These findings were associated with suppression of renal TGF-ß1 and mesangial connective tissue growth factor (CTGF) upregulation, inhibition of renal tissue inhibitor of metalloproteinase (TIMP)-1 expression, and reduction of renal interstitial myofibroblasts. In conclusion, our results suggest that hHGF gene therapy may be considered as an innovative therapeutic strategy to treat advanced diabetic nephropathy.

Address correspondence and reprint requests to Josep M. Cruzado MD, Nephrology Service, Hospital Universitari de Bellvitge, Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Catalonia, Spain. E-mail: 27541jcg{at}comb.es


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2004 by the American Diabetes Association.