Hepatocyte growth factor activator inhibitor types 1 and 2 are expressed by tubular epithelium in kidney and down-regulated in renal cell carcinoma

J Urol. 2004 Feb;171(2 Pt 1):890-6. doi: 10.1097/01.ju.0000092861.21122.d2.


Purpose: Hepatocyte growth factor (HGF) and its receptor MET have been implicated in kidney development and renal cell carcinoma (RCC) progression. HGF is secreted as an inactive proform and it must be activated to initiate MET signaling. HGF activator (HGFA) activates pro-HGF in injured tissue. We evaluated the expression of HGFA and its endogenous inhibitors HAI-1 and HAI-2 in normal kidney and RCC.

Materials and methods: We examined the gene expression of HGFA, HAI-1, HAI-2, HGF and MET in a normal kidney by laser captured microdissection, followed by reverse transcriptase-polymerase chain reaction. We also quantified the mRNA levels of these proteins in 14 RCC cases by real-time reverse transcriptase-polymerase chain reaction.

Results: HAI-1 and HAI-2 were abundant in the normal kidney. The uriniferous tubules showed the highest levels of HAI-1 and HAI-2 mRNA. HGFA was hardly detectable in the normal kidney. However, in the kidney with RCC a low but distinct level of HGFA mRNA became detectable in the tumor and adjacent renal tissue. The HAI-1 mRNA level was significantly and consistently down-regulated in RCC relative to normal tissue. HAI-2 mRNA was also significantly low in the advanced stage of RCC. MET was up-regulated in most cases of RCC.

Conclusions: HAI-1 and HAI-2 were expressed in renal tubular epithelial cells. The expression of the 2 HAIs was significantly down-regulated in RCC, whereas HGFA expression was enhanced in the diseased kidney, suggesting an imbalance between HAI and its target proteinases, including HGFA, in favor of proteinase activities in RCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism*
  • Down-Regulation*
  • Hepatocyte Growth Factor / biosynthesis
  • Hepatocyte Growth Factor / genetics
  • Humans
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism*
  • Kidney Tubules / metabolism*
  • Membrane Glycoproteins / biosynthesis*
  • Membrane Glycoproteins / genetics
  • Proteinase Inhibitory Proteins, Secretory
  • Proto-Oncogene Proteins c-met / biosynthesis
  • Proto-Oncogene Proteins c-met / genetics
  • RNA, Messenger / analysis
  • RNA, Messenger / biosynthesis
  • Serine Endopeptidases / biosynthesis
  • Serine Endopeptidases / genetics
  • Trypsin Inhibitor, Kunitz Soybean / biosynthesis*
  • Trypsin Inhibitor, Kunitz Soybean / genetics
  • Urothelium / metabolism


  • Membrane Glycoproteins
  • Proteinase Inhibitory Proteins, Secretory
  • RNA, Messenger
  • SPINT1 protein, human
  • SPINT2 protein, human
  • Hepatocyte Growth Factor
  • Trypsin Inhibitor, Kunitz Soybean
  • Proto-Oncogene Proteins c-met
  • HGF activator
  • Serine Endopeptidases