Hepatocyte growth factor-stimulating endothelial cell growth and accelerating glomerular capillary repair in experimental progressive glomerulonephritis.
Hepatocyte growth factor (HGF) is one of the major growth factors that stimulate the growth and the migration of vascular endothelial cells. In this study, we examined the beneficial effects of HGF for glomerular repair in an experimental progressive glomerulonephritis (GN) model prepared by injecting both anti-Thy-1.1 antibody (day 0) and habu-snake venom (day 1) in rats. The rats received continuous intraperitoneal administration of recombinant human HGF (80 microg/100 g/day) or vehicle control at an early stage (day 2 to day 9), after severe glomerular injury. The vehicle-infused control rats initially showed severe mesangiolysis with large ballooning (day 2), followed by the prominent proliferation of mesangial cells with minimal capillary regeneration (day 5 to week 2), and global sclerosis with chronic renal failure (week 4 to week 8). Although mesangiolysis with large ballooning and mesangial cell proliferation were also observed in the HGF-infused rats, glomerular capillary regeneration with marked endothelial cell proliferation occurred during HGF administration from day 2 to day 9. Subsequently, the glomerulus was repaired with the development of the capillary network and the reduction of mesangial hypercellularity from week 2 to week 4, and almost all of the glomeruli showed a normal structure by week 8. The HGF-treated rats showed significantly better renal functions (Cr: 0.3 +/- 0.1 vs. 3.5 +/- 1.1 mg/dl in control, p < 0.001), less proteinuria (21.2 +/- 8.0 mg/day vs. 421.4 +/- 45.1 mg/day in control, p < 0.001) and less glomerular sclerosis at week 8 than the vehicle-infused rats. We conclude that HGF accelerated glomerular repair through the growth of capillary endothelial cells and capillary regeneration in experimental progressive GN. Administering HGF is a logical and efficient strategy for treating progressive GN with severe capillary destruction.
Mori
Takahiro
T
Department of Pathology, Nippon Medical School, Tokyo, Japan. t_moritm@qa2.so-net.ne.jp
Shimizu
Akira
A
Masuda
Yukinari
Y
Fukuda
Yuh
Y
Yamanaka
Nobuaki
N
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000494:pharmacology; D002196:Capillaries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002455:Cell Division / Q000502:physiology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000473:pathology / Q000503:physiopathology*; D005920:Glomerular Mesangium / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology*; D005921:Glomerulonephritis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D007518:Isoantibodies / Q000009:adverse effects / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D008297:Male; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017841:Trimeresurus; D014757:Viper Venoms / Q000009:adverse effects / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D007518:Isoantibodies; D014757:Viper Venoms; C035678:anti-Thy antibody; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met