Hepatocyte growth factor gene therapy slows down the progression of diabetic nephropathy in db/db mice.
BACKGROUND
Effect of hepatocyte growth factor (HGF) has scarcely been determined on diabetic nephropathy.


METHODS
Adenovirus encoding human HGF gene or LacZ gene (as the control) was injected into the hindlimb muscles of the C57BL/KsJ-db/db (db/db) mice at the age of 12 weeks, a model of genetic diabetes. Diabetic nephropathy was then evaluated at the age of 24 weeks.


RESULTS
The urine volume and albumin excretion progressively decreased in the control, whereas they remained unchanged in the HGF-treated group during the 12-week follow-up. The HGF gene therapy did not affect glucose metabolism. However, it resulted in a better renal function as evaluated by creatinine clearance (Ccr) than the control; Ccr was progressively worsened in controls (0.14 +/- 0.02 liters/day) whereas unchanged in the HGF gene-treated group (0.38 +/- 0.09 liters/day, p < 0.05). Kidneys of the HGF gene-treated mice showed glomeruli with greater area and cell population, smaller glomerular sclerotic index, and less fibrosis in both glomeruli and renal tubules, where apoptotic rate of glomerular endothelial cells and that of tubular epithelial cells were significantly decreased. TGF-beta1 expression was significantly decreased in kidneys of the HGF gene-treated group. Finally, the HGF treatment significantly improved the long-term survival of db/db mice.


CONCLUSIONS
The HGF gene delivery thus appeared to slow down the aggravation of diabetic nephropathy in db/db mice by attenuating progression from the hyperfiltration phase into the sclerotic phase through antiapoptotic and antifibrotic actions. The present findings suggest that the HGF gene delivery can be a novel therapeutic approach against diabetic nephropathy.
Kagawa
Tomoyo
T
Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan.
Takemura
Genzou
G
Kosai
Ken-ichiro
K
Murata
Ichijiro
I
Ohno
Takamasa
T
Takahashi
Tomoyuki
T
Esaki
Masayasu
M
Maruyama
Rumi
R
Fujiwara
Takako
T
Ohashi
Hiroshige
H
Fujiwara
Hisayoshi
H
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004279:DNA, Viral / Q000008:administration & dosage; D003928:Diabetic Nephropathies / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000627:therapeutic use*; D006801:Humans; D007677:Kidney Function Tests; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000235:genetics / Q000627:therapeutic use; D012720:Severity of Illness Index; D014162:Transfection / Q000379:methods*; D016896:Treatment Outcome
D004279:DNA, Viral; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor