PMID- 14638904
OWN - NLM
STAT- MEDLINE
DCOM- 20040802
LR  - 20190607
IS  - 1046-6673 (Print)
IS  - 1046-6673 (Linking)
VI  - 14
IP  - 12
DP  - 2003 Dec
TI  - Hepatocyte growth factor modulates matrix metalloproteinases and plasminogen 
      activator/plasmin proteolytic pathways in progressive renal interstitial 
      fibrosis.
PG  - 3047-60
AB  - Evidence suggests that hepatocyte growth factor (HGF) ameliorates renal fibrosis 
      in animal models of chronic renal disease by promoting extracellular matrix 
      catabolism. This study examined the molecular mechanisms of HGF-induced 
      alterations in matrix degradation both in vitro and in vivo. In vitro, HGF 
      increased the collagen catabolizing activity of human proximal tubular epithelial 
      cells (HKC) that were treated with TGF-beta1. Increased collagen catabolism was 
      associated with enhanced activity of both matrix metalloproteinases (MMP) and 
      plasminogen activators (PA)/plasmin proteolytic pathways. HGF abrogated 
      TGF-beta1-induced production of the profibrotic tissue inhibitor of 
      metalloproteinase-2 (TIMP-2) and plasminogen activator inhibitor-1 (PAI-1). In 
      addition, HGF induced the production of MMP-9. In vivo, continuous infusion of 
      HGF in the rat remnant kidney model ameliorated renal fibrosis and 
      tubulointerstitial collagen deposition. This was associated with increased 
      tubular expression of MMP-9, enhanced in situ gelatinolytic activity, partially 
      restored plasmin activity and decreased expression of TIMP-2 and PAI-1 in tubular 
      cells, and upregulation of renal TIMP-3 expression. Conversely, blocking of 
      endogenous HGF by an anti-HGF neutralizing antibody increased renal fibrosis and 
      interstitial collagen. This was accompanied by decreased tubular expression of 
      MMP-9, less in situ proteolytic activity, and elevated expression of TIMP-2 and 
      PAI-1 in tubular cells. Collectively, these findings demonstrate that HGF 
      ameliorates renal fibrosis by enhancing extracellular matrix catabolism via both 
      MMP and the PA/plasmin proteolytic pathways.
FAU - Gong, Rujun
AU  - Gong R
AD  - Division of Renal Diseases, Department of Medicine, and Department of Pathology, 
      Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode 
      Island 02903, USA.
FAU - Rifai, Abdalla
AU  - Rifai A
FAU - Tolbert, Evelyn M
AU  - Tolbert EM
FAU - Centracchio, Jason N
AU  - Centracchio JN
FAU - Dworkin, Lance D
AU  - Dworkin LD
LA  - eng
GR  - R01-DK-52314/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Am Soc Nephrol
JT  - Journal of the American Society of Nephrology : JASN
JID - 9013836
RN  - 0 (Transforming Growth Factor beta)
RN  - 127497-59-0 (Tissue Inhibitor of Metalloproteinase-2)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 3.4.21.- (Plasminogen Activators)
RN  - EC 3.4.21.7 (Fibrinolysin)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Disease Progression
MH  - Fibrinolysin/*physiology
MH  - Fibrosis
MH  - Hepatocyte Growth Factor/*physiology
MH  - Humans
MH  - Kidney/cytology/metabolism/*pathology
MH  - Male
MH  - Matrix Metalloproteinase 9/biosynthesis
MH  - Matrix Metalloproteinases/*physiology
MH  - Plasminogen Activators/*physiology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Tissue Inhibitor of Metalloproteinase-2/physiology
MH  - Transforming Growth Factor beta/physiology
MH  - Urothelium/cytology/metabolism
EDAT- 2003/11/26 05:00
MHDA- 2004/08/03 05:00
CRDT- 2003/11/26 05:00
PHST- 2003/11/26 05:00 [pubmed]
PHST- 2004/08/03 05:00 [medline]
PHST- 2003/11/26 05:00 [entrez]
AID - 10.1097/01.asn.0000098686.72971.db [doi]
PST - ppublish
SO  - J Am Soc Nephrol. 2003 Dec;14(12):3047-60. doi: 
      10.1097/01.asn.0000098686.72971.db.