p66Shc mediates high-glucose and angiotensin II-induced oxidative stress renal tubular injury via mitochondrial-dependent apoptotic pathway

Lin Sun*, Li Xiao, Jing Nie, Fu You Liu, Guang Hui Ling, Xue Jing Zhu, Wen Bin Tang, Wen Cui Chen, Yun Cheng Xia, Ming Zhan, Ming Ming Ma, You Ming Peng, Hong Liu, Ying Hong Liu, Yashpal S. Kanwar

*Corresponding author for this work

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

p66Shc, a promoter of apoptosis, modulates oxidative stress response and cellular survival, but its role in the progression of diabetic nephropathy is relatively unknown. In this study, mechanisms by which p66Shc modulates high-glucose (HG)- or angiotensin (ANG) II-induced mitochondrial dysfunction were investigated in renal proximal tubular cells (HK-2 cells). Expression of p66Shc and its phosphorylated form (p-p66Shc, serine residue 36) and apoptosis were notably increased in renal tubules of diabetic mice, suggesting an increased reactive oxygen species production. In vitro, HG and ANG II led to an increased expression of total and p-p66Shc in HK-2 cells. These changes were accompanied with increased production of mitochondrial H2O2, reduced mitochondrial membrane potential, increased translocation of mitochondrial cytochrome c from mitochondria into cytosol, upregulation of the expression of caspase-9, and ultimately reduced cell survival. Overexpression of a dominant-negative Ser36 mutant p66Shc (p66ShcS36A) or treatment of p66Shc- or PKC-β-short interfering RNAs partially reversed these changes. Treatment of HK-2 cells with HG and ANG II also increased the protein-protein association between p-p66Shc and Pin1, an isomerase, in the cytosol, and with cytochrome c in the mitochondria. These interactions were partially disrupted with the treatment of PKC-β inhibitor or Pin1-short interfering RNA. These data suggest that p66Shc mediates HG- and ANG II-induced mitochondrial dysfunctions via PKC-β and Pin1-dependent pathways in renal tubular cells.

Original languageEnglish (US)
Pages (from-to)F1014-F1025
JournalAmerican Journal of Physiology - Renal Physiology
Volume299
Issue number5
DOIs
StatePublished - Nov 1 2010

Keywords

  • Diabetic nephropathy
  • Mitochondria
  • Proximal tuble cells
  • ROS

ASJC Scopus subject areas

  • Physiology
  • Urology

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    Sun, L., Xiao, L., Nie, J., Liu, F. Y., Ling, G. H., Zhu, X. J., Tang, W. B., Chen, W. C., Xia, Y. C., Zhan, M., Ma, M. M., Peng, Y. M., Liu, H., Liu, Y. H., & Kanwar, Y. S. (2010). p66Shc mediates high-glucose and angiotensin II-induced oxidative stress renal tubular injury via mitochondrial-dependent apoptotic pathway. American Journal of Physiology - Renal Physiology, 299(5), F1014-F1025. https://doi.org/10.1152/ajprenal.00414.2010