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Prasad Devarajan - One of the best experts on this subject based on the ideXlab platform.
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induction of renal tubular cell Apoptosis in focal segmental glomerulosclerosis roles of proteinuria and fas dependent pathways
Journal of The American Society of Nephrology, 2005Co-Authors: Elif Erkan, Clotilde D Garcia, Larry T Patterson, Jaya Mishra, Mark Mitsnefes, Frederick J. Kaskel, Prasad DevarajanAbstract: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.
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sirt1 protects against oxidative stress induced renal tubular cell Apoptosis by the bidirectional regulation of catalase expression
Biochemical and Biophysical Research Communications, 2008Co-Authors: Kazuhiro Hasegawa, Shu Wakino, Kyoko Yoshioka, Satoru Tatematsu, Yoshikazu Hara, Hitoshi Minakuchi, Naoki Washida, Hirobumi Tokuyama, Koichi Hayashi, Hiroshi ItohAbstract: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.
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macrophage deficiency of p38α mapk promotes Apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice
Journal of Clinical Investigation, 2009Co-Authors: Tracie A Seimon, Yibin Wang, Takafumi Senokuchi, Dorien M Schrijvers, George Kuriakose, Alan R Tall, Ira TabasAbstract: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.
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Role of ERO1-α-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced Apoptosis
Journal of Cell Biology, 2009Co-Authors: Gang Li, Heather Harding, King Tung Chin, Dorit Ron, Marco Mongillo, Andrew R. Marks, Ira TabasAbstract: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.
Wadi N Suki - One of the best experts on this subject based on the ideXlab platform.
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mechanism of chronic obstructive uropathy increased expression of Apoptosis promoting molecules
Kidney International, 2000Co-Authors: Yeong Jin Choi, David Sheikhhamad, Wadi N Suki, Elzbieta Baranowskadaca, Vinh Nguyen, Takehiko Koji, Christie M Ballantyne, Luan D TruongAbstract:Mechanism of chronic obstructive uropathy: Increased expression of Apoptosis-promoting molecules. Background We have demonstrated that renal tubular and interstitial cells undergo pronounced Apoptosis during the course of chronic obstructive uropathy (COU). Apoptosis is a complex cellular process consisting of multiple steps, each of which is mediated by families of related molecules. These families may include receptor/ligand molecules such as Fas, Fas ligand, tumor necrosis factor receptor-1 (TNFR-1), and TNF-related Apoptosis inducing ligand (TRAIL); signal transduction adapter molecules such as Fas-associated death domain (FADD), TNFR-1 associated death domain (TRADD), receptor-interacting protein (RIP), Fas-associated factor (FAF), and Fas-associated phosphatase (FAP); or effector molecules such as caspases. However, the mechanism of tubular cell Apoptosis, as well as the pathogenetic relevance of these Apoptosis-related molecules in COU, remains poorly understood. Methods Kidneys were harvested from sham-operated control mice and mice with COU created by left ureter ligation sacrificed in groups of three at days 4, 15, 30, and 45. To detect apoptotic tubular and interstitial cells, in situ end labeling of fragmented DNA was performed. To detect the expression of Apoptosis-related molecules, ribonuclease protection assay was used with specific antisense RNA probes for Fas, Fas ligand, TNFR-1, TRAIL, FADD, TRADD, RIP, FAF, FAP, and caspase-8. Immunostaining for Fas, Fas ligand, TRAIL, TRADD, RIP, and caspase-8 was also performed. To assess the role of these molecules in COU-associated renal cell Apoptosis, the frequencies of apoptotic tubular and interstitial cells were separately quantitated for each experimental time point, and their patterns of variation were correlated with those of Apoptosis-related molecules. Results The obstructed kidneys displayed increased Apoptosis of both tubular and interstitial cells. Tubular cell Apoptosis appeared at day 4 after ureter ligation, peaked (fivefold of control) at day 15, and decreased gradually until the end of the experiment. In contrast, interstitial cell Apoptosis sustained a progressive increase throughout the experiment. Apoptosis was minimal at all experimental time points for control and contralateral kidneys. Compared with control and contralateral kidneys, the ligated kidneys displayed a dynamic expression of mRNAs for many Apoptosis-related molecules, which included an up to threefold increase for Fas, Fas ligand, TNF-R1, TRAIL, TRADD, RIP, and caspase-8, and an up to twofold increase for FADD and FAP, but there was little change for FAF. These mRNAs increased between days 4 and 15, decreased until day 30, but then increased again until day 45. The rise and fall of mRNAs between days 4 and 30 paralleled a similar fluctuation in tubular cell Apoptosis in that period. The subsequent increase of mRNAs was correlated with a continuous rise of interstitial cell Apoptosis. We demonstrated a positive immunostaining for Fas and Fas ligand in the tubular cells at early time points as well as in interstitial inflammatory cells at later time points. Although increased expression of TRAIL, TRADD, RIP, and caspase-8 was noted in tubular cells, there was no staining for these molecules in interstitial cells. Conclusion The current study documents a dynamic expression of several molecules that are known to mediate the most crucial steps of Apoptosis. It implicates these molecules in COU-associated renal cell Apoptosis and in the pathogenesis of this condition. It also lays the foundation for interventional studies, including genetic engineering, to evaluate the molecular control of Apoptosis associated with COU.
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cell Apoptosis and proliferation in obstructive uropathy
Seminars in Nephrology, 1998Co-Authors: Luan D Truong, David Sheikhhamad, Subhendu Chakraborty, Wadi N SukiAbstract:: Distinct patterns of cell proliferation and Apoptosis have been recognized for tubular, interstitial, and glomerular cells in chronic obstructive uropathy (OU). In many experimental models of OU, tubular cell Apoptosis develops quickly after ureter ligation, peaks between 7 and 24 days postobtruction (about 30-fold of control), and tapers thereafter. Apoptosis initially involves the dilated collecting ducts, but subsequently spreads to other tubules. Tubular cell Apoptosis probably accounts for renal tissue loss in OU because a direct correlation between its degree and the decline in dry kidney weight is well-documented. Pronounced tubular cell proliferation occurs shortly after ureter ligation, peaks at about day 6 (60-fold above control), and quickly subsides to baseline. Because the peak of tubular cell proliferation immediately precedes the onset of tubular cell Apoptosis, a pathogenetic link may exist between these two processes. Interstitial cell Apoptosis occurs with an increasing frequency throughout the course of OU (up to 35-fold above control). Interstitial cell proliferation appears in a bimodal pattern with the early peak coinciding with that of tubular cell proliferation and consisting mostly of fibroblasts, whereas the later peak consists mostly of inflammatory cells. Glomerular cell Apoptosis and proliferation are not different from control, which explains, in part, the structural integrity of the glomeruli throughout the disease course. Although the general pathways of cell Apoptosis and proliferation are well known, the molecular control of these processes in OU is poorly understood. In addition, whether Apoptosis or proliferation of tubular and interstitial cells is differentially regulated remains to be studied. However, several molecules known to be activated or overexpressed in kidney with OU may modulate cell Apoptosis and proliferation. The relevant functions of these molecules include induction of Apoptosis (angiotensin II, reactive oxygen species, jun-N-terminal kinase, p53), inhibition of the cell cycle (transforming growth factor-beta, p21), inhibition of Apoptosis (clusterin, epidermal growth factor, insulin-like growth factor, bcl-2, osteopontin), or promotion of interstitial fibroblast proliferation (platelet-derived growth factor).
Luan D Truong - One of the best experts on this subject based on the ideXlab platform.
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mechanism of chronic obstructive uropathy increased expression of Apoptosis promoting molecules
Kidney International, 2000Co-Authors: Yeong Jin Choi, David Sheikhhamad, Wadi N Suki, Elzbieta Baranowskadaca, Vinh Nguyen, Takehiko Koji, Christie M Ballantyne, Luan D TruongAbstract:Mechanism of chronic obstructive uropathy: Increased expression of Apoptosis-promoting molecules. Background We have demonstrated that renal tubular and interstitial cells undergo pronounced Apoptosis during the course of chronic obstructive uropathy (COU). Apoptosis is a complex cellular process consisting of multiple steps, each of which is mediated by families of related molecules. These families may include receptor/ligand molecules such as Fas, Fas ligand, tumor necrosis factor receptor-1 (TNFR-1), and TNF-related Apoptosis inducing ligand (TRAIL); signal transduction adapter molecules such as Fas-associated death domain (FADD), TNFR-1 associated death domain (TRADD), receptor-interacting protein (RIP), Fas-associated factor (FAF), and Fas-associated phosphatase (FAP); or effector molecules such as caspases. However, the mechanism of tubular cell Apoptosis, as well as the pathogenetic relevance of these Apoptosis-related molecules in COU, remains poorly understood. Methods Kidneys were harvested from sham-operated control mice and mice with COU created by left ureter ligation sacrificed in groups of three at days 4, 15, 30, and 45. To detect apoptotic tubular and interstitial cells, in situ end labeling of fragmented DNA was performed. To detect the expression of Apoptosis-related molecules, ribonuclease protection assay was used with specific antisense RNA probes for Fas, Fas ligand, TNFR-1, TRAIL, FADD, TRADD, RIP, FAF, FAP, and caspase-8. Immunostaining for Fas, Fas ligand, TRAIL, TRADD, RIP, and caspase-8 was also performed. To assess the role of these molecules in COU-associated renal cell Apoptosis, the frequencies of apoptotic tubular and interstitial cells were separately quantitated for each experimental time point, and their patterns of variation were correlated with those of Apoptosis-related molecules. Results The obstructed kidneys displayed increased Apoptosis of both tubular and interstitial cells. Tubular cell Apoptosis appeared at day 4 after ureter ligation, peaked (fivefold of control) at day 15, and decreased gradually until the end of the experiment. In contrast, interstitial cell Apoptosis sustained a progressive increase throughout the experiment. Apoptosis was minimal at all experimental time points for control and contralateral kidneys. Compared with control and contralateral kidneys, the ligated kidneys displayed a dynamic expression of mRNAs for many Apoptosis-related molecules, which included an up to threefold increase for Fas, Fas ligand, TNF-R1, TRAIL, TRADD, RIP, and caspase-8, and an up to twofold increase for FADD and FAP, but there was little change for FAF. These mRNAs increased between days 4 and 15, decreased until day 30, but then increased again until day 45. The rise and fall of mRNAs between days 4 and 30 paralleled a similar fluctuation in tubular cell Apoptosis in that period. The subsequent increase of mRNAs was correlated with a continuous rise of interstitial cell Apoptosis. We demonstrated a positive immunostaining for Fas and Fas ligand in the tubular cells at early time points as well as in interstitial inflammatory cells at later time points. Although increased expression of TRAIL, TRADD, RIP, and caspase-8 was noted in tubular cells, there was no staining for these molecules in interstitial cells. Conclusion The current study documents a dynamic expression of several molecules that are known to mediate the most crucial steps of Apoptosis. It implicates these molecules in COU-associated renal cell Apoptosis and in the pathogenesis of this condition. It also lays the foundation for interventional studies, including genetic engineering, to evaluate the molecular control of Apoptosis associated with COU.
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cell Apoptosis and proliferation in obstructive uropathy
Seminars in Nephrology, 1998Co-Authors: Luan D Truong, David Sheikhhamad, Subhendu Chakraborty, Wadi N SukiAbstract:: Distinct patterns of cell proliferation and Apoptosis have been recognized for tubular, interstitial, and glomerular cells in chronic obstructive uropathy (OU). In many experimental models of OU, tubular cell Apoptosis develops quickly after ureter ligation, peaks between 7 and 24 days postobtruction (about 30-fold of control), and tapers thereafter. Apoptosis initially involves the dilated collecting ducts, but subsequently spreads to other tubules. Tubular cell Apoptosis probably accounts for renal tissue loss in OU because a direct correlation between its degree and the decline in dry kidney weight is well-documented. Pronounced tubular cell proliferation occurs shortly after ureter ligation, peaks at about day 6 (60-fold above control), and quickly subsides to baseline. Because the peak of tubular cell proliferation immediately precedes the onset of tubular cell Apoptosis, a pathogenetic link may exist between these two processes. Interstitial cell Apoptosis occurs with an increasing frequency throughout the course of OU (up to 35-fold above control). Interstitial cell proliferation appears in a bimodal pattern with the early peak coinciding with that of tubular cell proliferation and consisting mostly of fibroblasts, whereas the later peak consists mostly of inflammatory cells. Glomerular cell Apoptosis and proliferation are not different from control, which explains, in part, the structural integrity of the glomeruli throughout the disease course. Although the general pathways of cell Apoptosis and proliferation are well known, the molecular control of these processes in OU is poorly understood. In addition, whether Apoptosis or proliferation of tubular and interstitial cells is differentially regulated remains to be studied. However, several molecules known to be activated or overexpressed in kidney with OU may modulate cell Apoptosis and proliferation. The relevant functions of these molecules include induction of Apoptosis (angiotensin II, reactive oxygen species, jun-N-terminal kinase, p53), inhibition of the cell cycle (transforming growth factor-beta, p21), inhibition of Apoptosis (clusterin, epidermal growth factor, insulin-like growth factor, bcl-2, osteopontin), or promotion of interstitial fibroblast proliferation (platelet-derived growth factor).
