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Apoptosis

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Prasad Devarajan – One of the best experts on this subject based on the ideXlab platform.

  • induction of renal tubular cell Apoptosis in focal segmental glomerulosclerosis roles of proteinuria and fas dependent pathways
    Journal of The American Society of Nephrology, 2005
    Co-Authors: Elif Erkan, Prasad Devarajan, Clotilde D Garcia, Larry T Patterson, Jaya Mishra, Mark Mitsnefes, Frederick J. Kaskel

    Abstract:

    The hypothesis that Apoptosis represents a proximate mechanism by which tubule cells are damaged in FSGS was tested. Thirty kidney biopsy specimens from children with idiopathic early FSGS were studied retrospectively. Unexpected, Apoptosis was evident in both proximal and distal tubule cells. There was a significant correlation between the degree of proteinuria and the number of apoptotic cells. Fas protein was detected predominantly in the tubule cells that underwent Apoptosis. When compared with patients with other chronic proteinuric states, those with FSGS displayed a proliferation/ Apoptosis ratio in favor of proliferation in the glomerulus but dramatically in favor of Apoptosis in the tubules. When both proteinuria and Apoptosis were included in a stepwise logistic regression procedure, only Apoptosis was found to predict independently the development of ESRD. Prolonged incubation of cultured Madin-Darby canine kidney (distal/collecting) cells with albumin also resulted in a dose- and duration-dependent induction of Apoptosis and activation of the Fas pathway, lending support to the novel finding of distal tubule cell Apoptosis in patients with FSGS. The results indicate that an elevated tubule cell Apoptosis rate at the time of initial biopsy represents an independent predictor of progression to ESRD in patients with early FSGS.

Hiroshi Itoh – One of the best experts on this subject based on the ideXlab platform.

  • sirt1 protects against oxidative stress induced renal tubular cell Apoptosis by the bidirectional regulation of catalase expression
    Biochemical and Biophysical Research Communications, 2008
    Co-Authors: Kazuhiro Hasegawa, Shu Wakino, Kyoko Yoshioka, Satoru Tatematsu, Yoshikazu Hara, Hitoshi Minakuchi, Naoki Washida, Hirobumi Tokuyama, Koichi Hayashi, Hiroshi Itoh

    Abstract:

    Abstract NAD+-dependent protein deacetylase Sirt1 regulates cellular Apoptosis. We examined the role of Sirt1 in renal tubular cell Apoptosis by using HK-2 cells, proximal tubular cell lines with or without reactive oxygen species (ROS), H2O2. Without any ROS, Sirt1 inhibitors enhanced Apoptosis and the expression of ROS scavenger, catalase, and Sirt1 overexpression downregulated catalase. When Apoptosis was induced with H2O2, Sirt1 was upregulated with the concomitant increase in catalase expression. Sirt1 overexpression rescued H2O2-induced Apoptosis through the upregulation of catalase. H2O2 induced the nuclear accumulation of forkhead transcription factor, FoxO3a and the gene silencing of FoxO3a enhanced H2O2-induced Apoptosis. In conclusion, endogenous Sirt1 maintains cell survival by regulating catalase expression and by preventing the depletion of ROS required for cell survival. In contrast, excess ROS upregulates Sirt1, which activates FoxO3a and catalase leading to rescuing Apoptosis. Thus, Sirt1 constitutes a determinant of renal tubular cell Apoptosis by regulating cellular ROS levels.

Ira Tabas – One of the best experts on this subject based on the ideXlab platform.

  • macrophage deficiency of p38α mapk promotes Apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice
    Journal of Clinical Investigation, 2009
    Co-Authors: Tracie A Seimon, Yibin Wang, Takafumi Senokuchi, Dorien M Schrijvers, George Kuriakose, Alan R Tall, Ira Tabas

    Abstract:

    ER stress occurs in macrophage-rich areas of advanced atherosclerotic lesions and contributes to macrophage Apoptosis and subsequent plaque necrosis. Therefore, signaling pathways that alter ER stress–induced Apoptosis may affect advanced atherosclerosis. Here we placed Apoe–/– mice deficient in macrophage p38α MAPK on a Western diet and found that they had a marked increase in macrophage Apoptosis and plaque necrosis. The macrophage p38α–deficient lesions also exhibited a significant reduction in collagen content and a marked thinning of the fibrous cap, which suggests that plaque progression was advanced in these mice. Consistent with our in vivo data, we found that ER stress–induced Apoptosis in cultured primary mouse macrophages was markedly accelerated under conditions of p38 inhibition. Pharmacological inhibition or genetic ablation of p38 suppressed activation of Akt in cultured macrophages and in atherosclerotic lesions. In addition, inhibition of Akt enhanced ER stress–induced macrophage Apoptosis, and expression of a constitutively active myristoylated Akt blocked the enhancement of ER stress–induced Apoptosis that occurred with p38 inhibition in cultured cells. Our results demonstrate that p38α MAPK may play a critical role in suppressing ER stress–induced macrophage Apoptosis in vitro and advanced lesional macrophage Apoptosis in vivo.

  • Role of ERO1-α-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced Apoptosis
    Journal of Cell Biology, 2009
    Co-Authors: Gang Li, Marco Mongillo, King Tung Chin, Heather Harding, Dorit Ron, Andrew R. Marks, Ira Tabas

    Abstract:

    Endoplasmic reticulum (ER) stress-induced Apoptosis is involved in many diseases, but the mechanisms linking ER stress to Apoptosis are incompletely understood. Based on roles for C/EPB homologous protein (CHOP) and ER calcium release in Apoptosis, we hypothesized that Apoptosis involves the activation of inositol 1,4,5-triphosphate (IP3) receptor (IP3R) via CHOP-induced ERO1-alpha (ER oxidase 1 alpha). In ER-stressed cells, ERO1-alpha is induced by CHOP, and small interfering RNA (siRNA) knockdown of ERO1-alpha suppresses Apoptosis. IP3-induced calcium release (IICR) is increased during ER stress, and this response is blocked by siRNA-mediated silencing of ERO1-alpha or IP3R1 and by loss-of-function mutations in Ero1a or Chop. Reconstitution of ERO1-alpha in Chop(-/-) macrophages restores ER stress-induced IICR and Apoptosis. In vivo, macrophages from wild-type mice but not Chop(-/-) mice have elevated IICR when the animals are challenged with the ER stressor tunicamycin. Macrophages from insulin-resistant ob/ob mice, another model of ER stress, also have elevated IICR. These data shed new light on how the CHOP pathway of Apoptosis triggers calcium-dependent Apoptosis through an ERO1-alpha-IP3R pathway.