Hepatocyte growth factor, but not insulin-like growth factor I, protects podocytes against cyclosporin A-induced apoptosis

被引:63
作者
Fornoni, A
Li, H
Foschi, A
Striker, GE
Striker, LJ
机构
[1] Univ Miami, Sch Med, Dept Med, Renal Cell Biol Lab, Miami, FL 33101 USA
[2] Univ Miami, Sch Med, Dept Med, Div Pulm & Crit Care Med, Miami, FL 33101 USA
[3] Univ Pavia, Policlin San Matteo, IRCCS, Div Nephrol & Dialysis, I-27100 Pavia, Italy
关键词
D O I
10.1016/S0002-9440(10)63966-1
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Cyclosporin A (CsA) nephropathy is associated with altered expression of apoptosis regulatory genes such as Fas-ligand and Bcl-2 family members in the glomerular, tubulointerstitial, and vascular compartments. Both hepatocyte growth factor (HGF) and insulin-like growth factor (IGF-I) protect against apoptosis, and HGF specifically up-regulates Bcl-xL, a protein that regulates apoptosis. We investigated whether Bcl-xL and Fas/Fas-ligand were regulated by CsA in cultured podocytes and whether CsA-induced apoptosis was prevented by HGF or IGF-I, A murine podocyte cell line was treated with CsA in the presence or absence of HGF or IGF-I, Apoptosis was quantitated by ELISA and by flow cytometry; Bcl-xL, Pas, and Fas-ligand were measured by Western blotting. Inhibitors of MAP kinase/ERK kinase (MEK)-1 and of phosphatidylinositol 3'-kinase (PI3'-K) were used to determine the signaling pathways involved in Bcl-xL, regulation. Apoptosis was induced by CsA. in a dose- and time-dependent fashion. CsA also decreased Bcl-xL levels. HGF, but not IGF-I, prevented apoptosis and restored Bcl-xL. levels. The regulation of Bcl-xL. by HGF was mediated by the PIS'-K but not by the MEK-1 pathway. In summary, we showed that CsA induces apoptosis in podocytes, Apoptosis was prevented by pretreatment with HGF but not IGF-I. Decreased apoptosis appeared to be mediated by regulation of Bcl-xL via the PIS'-K pathway, Our data suggest that the effect of CsA on podocytes may contribute to the glomerular damage and that HGF could provide protection.
引用
收藏
页码:275 / 280
页数:6
相关论文
共 25 条
  • [1] Preventive effect of hepatocyte growth factor on acute side effects of cyclosporin A in mice
    Amaike, H
    Matsumoto, K
    Oka, T
    Nakamura, T
    [J]. CYTOKINE, 1996, 8 (05) : 387 - 394
  • [2] The IGF axis and programmed cell death
    Butt, AJ
    Firth, SM
    Baxter, RC
    [J]. IMMUNOLOGY AND CELL BIOLOGY, 1999, 77 (03) : 256 - 262
  • [3] BINDING OF INSULIN-LIKE GROWTH FACTOR-I BY GLOMERULAR ENDOTHELIAL AND EPITHELIAL-CELLS - FURTHER EVIDENCE FOR IGF-I ACTION IN THE RENAL GLOMERULUS
    CONTI, FG
    ELLIOT, SJ
    STRIKER, LJ
    STRIKER, GE
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1989, 163 (02) : 952 - 958
  • [4] Apoptosis and necrosis: Mechanisms of cell death induced by cyclosporine A in a renal proximal tubular cell line
    Healy, E
    Dempsey, M
    Lally, C
    Ryan, MP
    [J]. KIDNEY INTERNATIONAL, 1998, 54 (06) : 1955 - 1966
  • [5] The role of growth hormone and insulin-like growth factor I in the regulation of apoptosis
    Isgaard, J
    Tivesten, Å
    [J]. GROWTH HORMONE & IGF RESEARCH, 1999, 9 : 125 - 128
  • [6] Johnson DW, 1999, J PHARMACOL EXP THER, V289, P535
  • [7] Study of hepatocyte growth factor in cyclosporine-induced nephropathy
    Kasai, S
    Yoshimura, R
    Sugimura, K
    Ohyama, A
    Harimoto, K
    Kishimoto, T
    Yoshimura, N
    [J]. TRANSPLANTATION PROCEEDINGS, 1997, 29 (03) : 1724 - 1725
  • [8] Autocrine FGF-2 is responsible for the cell density-dependent susceptibility to apoptosis of HUVEC - A role of a calpain inhibitor-sensitive mechanism
    Kinoshita, M
    Shimokado, K
    [J]. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 1999, 19 (10) : 2323 - 2329
  • [9] Klein M, 1999, ANNU REV MED, V50, P1
  • [10] Hepatocyte growth factor promotes renal epithelial cell survival by dual mechanisms
    Liu, YH
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 1999, 277 (04) : F624 - F633