The Experts below are selected from a list of 321 Experts worldwide ranked by ideXlab platform
Prasad Devarajan - One of the best experts on this subject based on the ideXlab platform.
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Apoptotic Response to Albumin Overload: Proximal vs. Distal/Collecting Tubule Cells
American Journal of Nephrology, 2005Co-Authors: Elif Erkan, Prasad Devarajan, George J. SchwartzAbstract:End-stage renal disease due to proteinuric states has a great impact on the quality of life by necessitating renal replacement therapy. Understanding the pathophysiologic consequences of Proteinuria i
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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, Prasad Devarajan, Clotilde D Garcia, Larry T Patterson, Jaya Mishra, Mark Mitsnefes, Frederick J KaskelAbstract: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.
Elif Erkan - One of the best experts on this subject based on the ideXlab platform.
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Proteinuria and progression of glomerular diseases
Pediatric Nephrology, 2013Co-Authors: Elif ErkanAbstract:One of the major challenges of nephrology is to develop therapeutic strategies to halt the progression of kidney diseases. In clinical settings, nephrotic-range Proteinuria correlates with the rate of progression, particularly in glomerular diseases. Hence, the degree of Proteinuria has been utilized to monitor the response to treatment as well as to predict outcome. However, the pathophysiology of Proteinuria-induced progression remains unknown. Albumin accounts for the majority of the protein in nephrotic urine and as a result of this clinical observation studies have focused on understanding the adverse effects of albumin overload in the kidney. Albumin is internalized by receptor-mediated endocytosis in proximal tubule cells via low density lipoprotein (LDL) type receptor, megalin. Albumin at high concentrations mimicking nephrotic milieu has resulted in the upregulation of pro-inflammatory/fibrogenic genes and apoptosis in proximal tubule cells in in vivo and in vitro models of albumin overload. These properties of albumin on proximal tubule cells may explain extensive tubulointerstitial fibrosis and tubular atrophy observed in end-stage kidney disease. In addition to tubular toxicity, podocytes respond to proteinuric states by cytoskeletal alterations and loss of the differentiation marker synaptopodin. Identifying the molecular network of proteins involved in albumin handling will enable us to manipulate the specific signaling pathways and prevent damage caused by Proteinuria.
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Apoptotic Response to Albumin Overload: Proximal vs. Distal/Collecting Tubule Cells
American Journal of Nephrology, 2005Co-Authors: Elif Erkan, Prasad Devarajan, George J. SchwartzAbstract:End-stage renal disease due to proteinuric states has a great impact on the quality of life by necessitating renal replacement therapy. Understanding the pathophysiologic consequences of Proteinuria i
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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, Prasad Devarajan, Clotilde D Garcia, Larry T Patterson, Jaya Mishra, Mark Mitsnefes, Frederick J KaskelAbstract: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.
Guangju Guan - One of the best experts on this subject based on the ideXlab platform.
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trb3 mediates renal tubular cell apoptosis associated with Proteinuria
Clinical and Experimental Medicine, 2015Co-Authors: Weiwei Wang, Jing Cheng, Shasha Lv, Guangju GuanAbstract:Proteinuria may contribute to progressive renal damage by inducing tubulointerstitial inflammation, fibrosis and tubular cell apoptosis, but the underlying mechanisms remain largely unknown. TRB3 is a kinase-like molecule that can modify cellular survival and interfere with signal transduction pathways. We seek to determine the role of TRB3 in renal tubular cell apoptosis associated with Proteinuria. Herein, we reported that in a rat tubular cell line, high concentration of albumin augmented TRB3 expression and induced apoptosis, while TRB3 silencing with special small interference RNA significantly attenuated apoptosis. In addition, we found that albumin-induced apoptosis was related to inhibition of Akt phosphorylation, which was, however, partially reversed by TRB3 silencing, indicating that TRB3 worked through Akt pathway in this apoptotic signaling cascade. In vivo, we observed increased TRB3 expression in kidneys of streptozotocin-induced diabetic nephropathy model and albumin-overload nephropathy model, both of which showed overt Proteinuria. Notably, Proteinuria induced apoptosis in renal tubules, which was less severe after genetically inhibition of TRB3. Taken together, these results suggest that TRB3 mediates renal tubular cell apoptosis induced by protein overload, broadening our understanding of the pathogenesis of progressive proteinuric kidney diseases.
Jaakko Patrakka - One of the best experts on this subject based on the ideXlab platform.
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new insights into the role of podocytes in Proteinuria
Nature Reviews Nephrology, 2009Co-Authors: Jaakko Patrakka, Karl TryggvasonAbstract:The fact that numerous systemic and renal disorders result in progressive Proteinuria illustrates the importance of the glomerular filtration barrier. In this concise Review, authors from Stockholm provide an update on the structure and function of the glomerular filtration barrier and the pathogenesis of Proteinuria, with a particular emphasis on the involvement of podocytes. The discussion encompasses newly identified pathogenic players, including TRPC6, phospholipase C e, MYH9 and the urokinase receptor. Disturbances in many different molecular pathways and interactions can lead to the same clinical end points of Proteinuria and end-stage renal disease. Proteinuria is often accompanied by a cytopathological change in the glomerulus that is referred to as effacement (retraction) of the podocyte foot processes. The molecular mechanisms that lead to Proteinuria and podocyte effacement are poorly understood; therefore, targeted therapies are lacking. During the past 5 years, however, a large body of data has emerged in this field. The discovery of podocyte gene defects that underlie some hereditary proteinuric syndromes has changed our understanding of the relative contributions of components of the glomerular filter. Furthermore, pathogenic pathways activated in podocytes during Proteinuria have been identified. Together, these findings pinpoint the podocyte as the most obvious candidate for therapeutic intervention. In the near future, the use of large-scale expression profiling platforms, transgenic mouse lines, and other in vivo gene delivery methods will further expand our understanding of the pathology of the glomerular filtration barrier, and perhaps reveal novel target molecules for the therapy of proteinuric kidney diseases.
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The Number of Podocyte Slit Diaphragms Is Decreased in Minimal Change Nephrotic Syndrome
Pediatric Research, 2002Co-Authors: Jaakko Patrakka, Anne-tiina Lahdenkari, Olli Koskimies, Christer Holmberg, Jorma Wartiovaara, Hannu JalankoAbstract:The pathophysiology of Proteinuria in acquired kidney diseases is mostly unknown. Recent findings in genetic renal diseases suggest that glomerular epithelial cells (podocytes) and the slit diaphragm connecting the podocyte foot processes play an important role in the development of Proteinuria. In this work we systematically evaluated the podocyte slit pores by transmission electron microscopy in two important nephrotic diseases, minimal change nephrotic syndrome (MCNS) and membranous nephropathy (MN). As controls, we used kidneys with tubulointerstitial nephritis (TIN). Effacement of podocyte foot processes was evident in proteinuric kidneys. However, quite normal looking foot processes and slit pores with varying width were also observed. Careful analysis of slit pores revealed, that the proportion of the pores spanned by the linear image of slit diaphragm, was reduced by 39% in kidneys from MCNS patients (1265 pores analyzed) compared with TIN samples (902 pores analyzed, p = 0.0003). To enhance the detection rate of the slit diaphragms, the “empty” podocyte pores were further analyzed with tilting series from −45 to +45. This revealed the linear diaphragm image in 71% and 26% of the slits in TIN and MCNS kidneys, respectively ( p = 0.0003). In contrast to findings in MCNS, no significant reduction of the slit diaphragms were seen in MN kidneys compared with the controls. The results suggest that MCNS is associated with disruption of glomerular slit diaphragms.
Zheng Dong - One of the best experts on this subject based on the ideXlab platform.
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pkc δ promotes renal tubular cell apoptosis associated with Proteinuria
Journal of The American Society of Nephrology, 2010Co-Authors: Xiaoning Li, Navjotsingh Pabla, Guie Dong, Robert O Messing, Cong Yi Wang, Zheng DongAbstract:Proteinuria may contribute to progressive renal damage by inducing tubulointerstitial inflammation, fibrosis, and tubular cell injury and death, but the mechanisms underlying these pathologic changes remain largely unknown. Here, in a rat kidney proximal tubular cell line (RPTC), albumin induced apoptosis in a time- and dose-dependent manner. Caspase activation accompanied albumin-induced apoptosis, and general caspase inhibitors could suppress this activation. In addition, Bcl-2 transfection inhibited apoptosis and attenuated albumin-induced Bax translocation to mitochondria and cytochrome c release from the organelles, further confirming a role for the intrinsic pathway of apoptosis in albuminuria-associated tubular apoptosis. We observed phosphorylation and activation of PKC-δ early during treatment of RPTC cells with albumin. Rottlerin, a pharmacologic inhibitor of PKC-δ, suppressed albumin-induced Bax translocation, cytochrome c release, and apoptosis. Moreover, a dominant-negative mutant of PKC-δ blocked albumin-induced apoptosis in RPTC cells. In vivo, we observed activated PKC-δ in proteinuric kidneys of streptozotocin-induced diabetic mice and in kidneys after direct albumin overload. Notably, albumin overload induced apoptosis in renal tubules, which was less severe in PKC-δ-knockout mice. Taken together, these results suggest that activation of PKC-δ promotes tubular cell injury and death during albuminuria, broadening our understanding of the pathogenesis of progressive proteinuric kidney diseases.
