p66Shc mediates high-glucose and angiotensin II-induced oxidative stress renal tubular injury via mitochondrial-dependent apoptotic pathway
| Autor: | Jing Nie, Youming Peng, Xue Jing Zhu, Wen Cui Chen, Hong Liu, Lin Sun, Guang hui Ling, Wen Bin Tang, Yashpal S. Kanwar, Yun Cheng Xia, Fu You Liu, Li Xiao, Ming Ming Ma, Ying hong Liu, Ming Zhan |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
medicine.medical_specialty
Src Homology 2 Domain-Containing Transforming Protein 1 Physiology Apoptosis Mitochondrion Biology medicine.disease_cause DNA Mitochondrial Diabetes Mellitus Experimental Mice chemistry.chemical_compound Malondialdehyde Internal medicine Protein Kinase C beta In Situ Nick-End Labeling medicine Animals RNA Small Interfering Protein Kinase C Peptidylprolyl isomerase chemistry.chemical_classification Mice Inbred ICR Reactive oxygen species Microscopy Confocal L-Lactate Dehydrogenase Angiotensin II Articles Peptidylprolyl Isomerase Mitochondria Cell biology NIMA-Interacting Peptidylprolyl Isomerase Oxidative Stress Glucose Kidney Tubules Endocrinology Gene Expression Regulation Shc Signaling Adaptor Proteins chemistry Signal transduction Reactive Oxygen Species Oxidative stress Signal Transduction |
| Zdroj: | American Journal of Physiology-Renal Physiology. 299:F1014-F1025 |
| ISSN: | 1522-1466 1931-857X |
| DOI: | 10.1152/ajprenal.00414.2010 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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