| Authors |
Lau GJ, Godin N, Maachi H, Lo CS, Wu SJ, Zhu JX, Brezniceanu ML, Chénier I,
Fragasso-Marquis J, Lattouf JB, Ethier J, Filep JG, Ingelfinger JR, Nair V,
Kretzler M, Cohen CD, Zhang SL, Chan JS
|
| Submitted By |
Matthias Kretzler on 10/31/2012 |
| Status |
Published |
| Journal |
Diabetes |
| Year |
2012 |
| Date Published |
2/1/2012 |
| Volume : Pages |
61 : 474 - 484 |
| PubMed Reference |
22210314 |
| Abstract |
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 (RPTCs) 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 RPTCs 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
RPTs of db/db mice compared with db/m+ and db/db 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 RPTCs. More important, enhanced Bmf
expression was detected in RPTs 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.
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