Hepatocyte growth factor in renal failure: Promise and reality

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Presentation transcript:

Hepatocyte growth factor in renal failure: Promise and reality Gustavo A. Vargas, Andreas Hoeflich, PD Dr Peter M. Jehle Kidney International Volume 57, Issue 4, Pages 1426-1436 (April 2000) DOI: 10.1046/j.1523-1755.2000.00987.x Copyright © 2000 International Society of Nephrology Terms and Conditions

Figure 1 Molecular structure of the hepatocyte growth factor (HGF) receptor c-met (A) and signal transduction (B). (A) The c-met product (left) is a tyrosine kinase receptor of 190 kD with two disulfide-linked subunits, a 50 kD extracellular α-chain (α) and a 145 kD β-chain (β). HGF binding induces receptor dimerization (middle) and autophosphorylation (right). (B) After autoposphorylation in the kinase domain of c-met (Tyr1234, Tyr1235; indicated as Y in the white box), a downstream located multifunctional docking site (Tyr1349, Tyr1356) in the C-terminal domain mediates the signal to multiple transducers, including PI3 kinase, the Grb2/Sos/Ras complex, the IRS-like multiadaptor protein Gab-1, phospholipase-γ, and probably Src. The pleiotropic effects of HGF are mediated via different signaling pathways, which may differ in various cell types. Kidney International 2000 57, 1426-1436DOI: (10.1046/j.1523-1755.2000.00987.x) Copyright © 2000 International Society of Nephrology Terms and Conditions

Figure 2 Morphogenic effects of HGF on cultured proximal tubular cells. The differentiated rabbit proximal tubular cell line PT-1 was cultured in Dulbecco's modified Eagle's medium (DMEM) as described94,95. Cells were incubated for 48 hours in serum-free medium alone (A; bar = 10 μm) or in the presence of HGF (10-9 mol/L; B). HGF induced cell scattering (thin arrows) and tubulogenesis (thick arrows). Reprinted with permission from Jehle et al94. Kidney International 2000 57, 1426-1436DOI: (10.1046/j.1523-1755.2000.00987.x) Copyright © 2000 International Society of Nephrology Terms and Conditions

Figure 3 Stimulation of c-met gene expression by cytokines and growth factors in cultured renal epithelial cells. Mouse inner medullary collecting duct epithelial cells (mIMCD-3) were incubated for 24 hours in serum-free medium without (control) or with specific cytokines or growth factors at a concentration of 10 ng/mL. The total cellular RNA was isolated and hybridized using rat c-met cDNA as a probe. The same blot was stripped and reprobed with GAPDH to confirm equal loading of the RNA. Similar results were obtained using proximal tubule-derived opossum kidney epithelial cells. Reprinted with permission from Liu et al116. Kidney International 2000 57, 1426-1436DOI: (10.1046/j.1523-1755.2000.00987.x) Copyright © 2000 International Society of Nephrology Terms and Conditions

Figure 4 Endothelin-1 release by cultured proximal tubular (PT-1) cells, coincubated with cyclosporine A and hepatocyte growth factor (HGF, 10-8 mol/L) or epidermal growth factor (EGF, 10-8 mol/L). Data are means ± SEM, N = 6. ***P < 0.001 vs. cyclosporine 50 μg/L; +++P < 0.001 vs. cyclosporine 500 μg/L. Reprinted with permission from Haug et al132. Kidney International 2000 57, 1426-1436DOI: (10.1046/j.1523-1755.2000.00987.x) Copyright © 2000 International Society of Nephrology Terms and Conditions