Endogenous hepatocyte growth factor ameliorates chronic renal injury by activating matrix degradation pathways.
BACKGROUND
Hepatocyte growth factor (HGF) has been shown to promote tubule repair and renal regeneration following acute injury; however, whether HGF also modulates the development and progression of chronic renal diseases that are characterized by progressive tissue fibrosis is uncertain. To examine this question, this study investigated the functional consequence of blocking endogenous HGF signaling in vivo in a model of chronic renal disease. The effects of HGF on the processes of matrix synthesis and degradation in cultured renal epithelial cells were also examined.


METHODS
The level of activity of the HGF/c-met axis was examined in rats following 5/6 nephrectomy at multiple time points. To determine the effects of HGF in modulating chronic renal injury, HGF action was blocked in remnant kidney rats using an anti-HGF antibody. The effects of HGF on extracellular matrix (ECM) synthesis and degradation were examined in renal epithelial cells by (35)S-methionine labeling, Western blotting, and zymographic analysis.


RESULTS
An increase in renal and systemic production of HGF coupled with an increase in renal c-met was observed in rats with remnant kidneys. When HGF action was blocked by the administration of an anti-HGF antibody, rats experienced a rapid decrease in glomerular filtration rate and increased renal fibrosis. Kidney sections from the antibody-treated rats displayed a marked increase in ECM accumulation and in alpha-smooth muscle actin-positive cells in both the interstitium and tubular epithelium. In vitro studies revealed that HGF reduced net ECM accumulation by human proximal tubule cells (HKC), and this effect was abolished by incubating cells with an anti-HGF antibody. HGF did not alter the ECM synthetic rate in HKC cells. Rather, it markedly increased collagenase such as matrix metalloproteinase-9 (MMP-9) protein expression, as evidenced by Western blotting and zymographic analysis. HGF also decreased the expression of tissue inhibitors of matrix metalloproteinase-1 (TIMP-1) and TIMP-2, the endogenous inhibitors of MMPs.


CONCLUSIONS
These results suggest that HGF is a potent antifibrogenic factor both in vitro and in vivo. Endogenous activation of HGF tends to preserve kidney structure and function in rats with chronic renal disease by activating matrix degradation pathways.
Liu
Y
Y
Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA. liuy@msx.upmc.edu
Rajur
K
K
Tolbert
E
E
Dworkin
L D
LD
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002478:Cells, Cultured; D002908:Chronic Disease; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000503:physiopathology; D005109:Extracellular Matrix / Q000201:enzymology / Q000378:metabolism*; D005355:Fibrosis / Q000209:etiology; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D009392:Nephrectomy / Q000379:methods; D010447:Peptide Hydrolases / Q000378:metabolism; D010641:Phenotype; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D019714:Tissue Inhibitor of Metalloproteinases / Q000037:antagonists & inhibitors
D000906:Antibodies; D019714:Tissue Inhibitor of Metalloproteinases; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D010447:Peptide Hydrolases; D008666:Metalloendopeptidases