title: p66Shc mediates high-glucose and angiotensin II-induced oxidative stress renal tubular injury via mitochondrial-dependent apoptotic pathway.
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 H(2)O(2), 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.
authors.affiliation: Dept. of Nephrology, 2nd Xiangya Hospital, Central South Univ., No. 139 Renmin Middle Rd., Changsha, Hunan 410011. l-sun3@northwestern.edu
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
authors.forename: Li
authors.initials: L
authors.lastname: Xiao
authors.forename: Jing
authors.initials: J
authors.lastname: Nie
authors.forename: Fu-You
authors.initials: FY
authors.lastname: Liu
authors.forename: Guang-Hui
authors.initials: GH
authors.lastname: Ling
authors.forename: Xue-Jing
authors.initials: XJ
authors.lastname: Zhu
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Tang
authors.forename: Wen-Cui
authors.initials: WC
authors.lastname: Chen
authors.forename: Yun-Cheng
authors.initials: YC
authors.lastname: Xia
authors.forename: Ming
authors.initials: M
authors.lastname: Zhan
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Ma
authors.forename: You-Ming
authors.initials: YM
authors.lastname: Peng
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Ying-Hong
authors.initials: YH
authors.lastname: Liu
authors.forename: Yashpal S
authors.initials: YS
authors.lastname: Kanwar
mesh_terms: D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D004272:DNA, Mitochondrial / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000633:toxicity*; D020287:In Situ Nick-End Labeling; D007684:Kidney Tubules / Q000473:pathology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000502:physiology*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D018384:Oxidative Stress / Q000502:physiology*; D019696:Peptidylprolyl Isomerase / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: D004272:DNA, Mitochondrial; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D000804:Angiotensin II; D008315:Malondialdehyde; D007770:L-Lactate Dehydrogenase; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; D005947:Glucose