Bcl-2-Modifying Factor Induces Renal Proximal Tubular Cell Apoptosis in Diabetic Mice

被引:46
作者
Lau, Garnet J. [1 ]
Godin, Nicolas [1 ]
Maachi, Hasna [1 ]
Lo, Chao-Sheng [1 ]
Wu, Shyh-Jong [1 ]
Zhu, Jian-Xin [1 ]
Brezniceanu, Marie-Luise [1 ]
Chenier, Isabelle [1 ]
Fragasso-Marquis, Joelle [1 ]
Lattouf, Jean-Baptiste [1 ]
Ethier, Jean [1 ]
Filep, Janos G. [2 ]
Ingelfinger, Julie R. [3 ]
Nair, Viji [4 ]
Kretzler, Matthias [4 ]
Cohen, Clemens D. [5 ]
Zhang, Shao-Ling [1 ]
Chan, John S. D. [1 ]
机构
[1] Univ Montreal, Hotel Dieu Hosp, CRCHUM, Montreal, PQ, Canada
[2] Maisonneuve Rosemont Hosp, Res Ctr, Montreal, PQ, Canada
[3] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Nephrol Unit, Boston, MA USA
[4] Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA
[5] Univ Zurich, Inst Physiol, Univ Zurich Hosp, Div Nephrol, Zurich, Switzerland
基金
美国国家卫生研究院; 加拿大健康研究院;
关键词
ANGIOTENSINOGEN GENE-EXPRESSION; GLOMERULOTUBULAR JUNCTION ABNORMALITIES; ATUBULAR GLOMERULI; KIDNEY; NEPHROPATHY; BMF; OVEREXPRESSION; ACTIVATION; INJURY; BIM;
D O I
10.2337/db11-0141
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
This study investigated the mechanisms underlying tubular apoptosis in diabetes by identifying proapoptotic genes that are differentially upregulated by reactive oxygen species in renal proximal tubular cells (RFTCs) in models of diabetes. Total RNAs isolated from renal proximal tubules (RPTs) of 20-week-old heterozygous db/m+, db/db, and db/db catalase (CAT)-transgenic (Tg) mice were used for DNA chip microarray analysis. Real-time quantitative PCR assays, immunohistochemistry, and mice rendered diabetic with streptozotocin were used to validate the proapoptotic gene expression in RPTs. Cultured rat RFTCs were used to confirm the apoptotic activity and regulation of proapoptotic gene expression. Additionally, studies in kidney tissues from patients with and without diabetes were used to confirm enhanced proapoptotic gene expression in RPTs. Bcl-2-modifying factor (Bmf) was differentially upregulated (P < 0.01) in RFTs of db/db mice compared with db/m+ and dbldb CAT-Tg mice and in RPTs of streptozotocin-induced diabetic mice in which insulin reversed this finding. In vitro, Bmf cDNA overexpression in rat RPTCs coimmunoprecipated with Bcl-2, enhanced caspase-3 activity, and promoted apoptosis. High glucose (25 mmol/L) induced Bmf mRNA expression in RPTCs, whereas rotenone, catalase, diphenylene iodinium, and apocynin decreased it. Knockdown of Bmf' with small interfering RNA reduced high glucose induced apoptosis in RFTCs. More important, enhanced Bmf expression was detected in RFTs of kidneys from patients with diabetes. These data demonstrate differential upregulation of Bmf in diabetic RPTs and suggest a potential role for Bmf in regulating RPTC apoptosis and tubular atrophy in diabetes. Diabetes 61:474-484, 2012
引用
收藏
页码:474 / 484
页数:11
相关论文
共 42 条
  • [1] High glucose-induced oxidative stress causes apoptosis in proximal tubular epithelial cells and is mediated by multiple caspases
    Allen, DA
    Harwood, SM
    Varagunam, M
    Raftery, MJ
    Yaqoob, MM
    [J]. FASEB JOURNAL, 2003, 17 (03) : 908 - +
  • [2] Gene Ontology: tool for the unification of biology
    Ashburner, M
    Ball, CA
    Blake, JA
    Botstein, D
    Butler, H
    Cherry, JM
    Davis, AP
    Dolinski, K
    Dwight, SS
    Eppig, JT
    Harris, MA
    Hill, DP
    Issel-Tarver, L
    Kasarskis, A
    Lewis, S
    Matese, JC
    Richardson, JE
    Ringwald, M
    Rubin, GM
    Sherlock, G
    [J]. NATURE GENETICS, 2000, 25 (01) : 25 - 29
  • [3] Kidneys sans glomeruli
    Beyenbach, KW
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2004, 286 (05) : F811 - F827
  • [4] Catalase overexpression attenuates angiotensinogen expression and apoptosis in diabetic mice
    Brezniceanu, M.-L.
    Liu, F.
    Wei, C.-C.
    Tran, S.
    Sachetelli, S.
    Zhang, S.-L.
    Guo, D.-F.
    Filep, J. G.
    Ingelfinger, J. R.
    Chan, J. S. D.
    [J]. KIDNEY INTERNATIONAL, 2007, 71 (09) : 912 - 923
  • [5] Transforming growth factor-beta 1 stimulates angiotensinogen gene expression in kidney proximal tubular cells
    Brezniceanu, M-L
    Wei, C-C
    Zhang, S-L
    Hsieh, T-J
    Guo, D-F
    Hebert, M-J
    Ingelfinger, J. R.
    Filep, J. G.
    Chan, J. S. D.
    [J]. KIDNEY INTERNATIONAL, 2006, 69 (11) : 1977 - 1985
  • [6] Attenuation of interstitial fibrosis and tubular apoptosis in db/db transgenic mice overexpressing catalase in renal proximal tubular cells
    Brezniceanu, Marie-Luise
    Liu, Fang
    Wei, Chih-Chang
    Chenier, Isabelle
    Godin, Nicolas
    Zhang, Shao-Ling
    Filep, Janos G.
    Ingelfinger, Julie R.
    Chan, John S. D.
    [J]. DIABETES, 2008, 57 (02) : 451 - 459
  • [7] Quantitative gene expression analysis in renal biopsies:: A novel protocol for a high-throughput multicenter application
    Cohen, CD
    Frach, K
    Schlöndorff, D
    Kretzler, M
    [J]. KIDNEY INTERNATIONAL, 2002, 61 (01) : 133 - 140
  • [8] Kidney expression of glutathione peroxidase-1 is not protective against streptozotocin-induced diabetic nephropathy
    de Haan, JB
    Stefanovic, N
    Nikolic-Paterson, D
    Scurr, LL
    Croft, KD
    Mori, TA
    Hertzog, P
    Kola, I
    Atkins, RC
    Tesch, GH
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2005, 289 (03) : F544 - F551
  • [9] The kidney androgen-regulated protein promoter confers renal proximal tubule cell-specific and highly androgen-responsive expression on the human angiotensinogen gene in transgenic mice
    Ding, YM
    Davisson, RL
    Hardy, DO
    Zhu, LJ
    Merrill, DC
    Catterall, JF
    Sigmund, CD
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (44) : 28142 - 28148
  • [10] The early natural history of nephropathy in type 1 diabetes - II. Early renal structural changes in type 1 diabetes
    Drummond, K
    Mauer, M
    [J]. DIABETES, 2002, 51 (05) : 1580 - 1587