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10.1371/journal.pone.0063506 http://scihub22266oqcxt.onion/10.1371/journal.pone.0063506 23691056!3656911!23691056     free     free     free Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       PLoS+One 2013 ; 8 (5): e63506 Nephropedia Template TP {{tp|p=23691056|t=2013. Dysregulated autophagy contributes to podocyte damage in Fabry s disease |pdf=|usr=}}{{23691056}} gab.com Text Dysregulated autophagy contributes to podocyte damage in Fabry s disease JO: PLoS One http://www.kidney.de/pget.php?&tw=1&pmid=23691056 #FOAvip Fabry's disease results from an inborn error of glycosphingolipid metabolism that is due to deficiency of the lysosomal hydrolase alpha-galactosidase A. This X-linked defect results in the accumulation of enzyme substrates with terminally alpha-glycosidically bound galactose, mainly the neutral glycosphingolipid Globotriaosylceramide (Gb3) in various tissues, including the kidneys. Although end-stage renal disease is one of the most common causes of death in hemizygous males with Fabry's disease, the pathophysiology leading to proteinuria, hematuria, hypertension, and kidney failure is not well understood. Histological studies suggest that the accumulation of Gb3 in podocytes plays an important role in the pathogenesis of glomerular damage. However, due to the lack of appropriate animal or cellular models, podocyte damage in Fabry's disease could not be directly studied yet. As murine models are insufficient, a human model is needed. Here, we developed a human podocyte model of Fabry's disease by combining RNA interference technology with lentiviral transduction of human podocytes. Knockdown of alpha-galactosidase A expression resulted in diminished enzymatic activity and slowly progressive accumulation of intracellular Gb3. Interestingly, these changes were accompanied by an increase in autophagosomes as indicated by an increased abundance of LC3-II and a loss of mTOR kinase activity, a negative regulator of the autophagic machinery. These data suggest that dysregulated autophagy in alpha-galactosidase A-deficient podocytes may be the result of deficient mTOR kinase activity. This finding links the lysosomal enzymatic defect in Fabry's disease to deregulated autophagy pathways and provides a promising new direction for further studies on the pathomechanism of glomerular injury in Fabry patients. Twit Text FOAVip Dysregulated autophagy contributes to podocyte damage in Fabry s disease ????PLoS One http://www.kidney.de/pget.php?&tw=1&pmid=23691056 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=23691056 #FOAvip English Wikipedia <ref>{{Cite pmid|23691056}}</ref> Dysregulated autophagy contributes to podocyte damage in Fabry s disease #MMPMID23691056 Liebau MC; Braun F; Hopker K; Weitbrecht C; Bartels V; Muller RU; Brodesser S; Saleem MA; Benzing T; Schermer B; Cybulla M; Kurschat CE PLoS One 2013[]; 8 (5): e63506 PMID23691056show ga Fabry's disease results from an inborn error of glycosphingolipid metabolism that is due to deficiency of the lysosomal hydrolase alpha-galactosidase A. This X-linked defect results in the accumulation of enzyme substrates with terminally alpha-glycosidically bound galactose, mainly the neutral glycosphingolipid Globotriaosylceramide (Gb3) in various tissues, including the kidneys. Although end-stage renal disease is one of the most common causes of death in hemizygous males with Fabry's disease, the pathophysiology leading to proteinuria, hematuria, hypertension, and kidney failure is not well understood. Histological studies suggest that the accumulation of Gb3 in podocytes plays an important role in the pathogenesis of glomerular damage. However, due to the lack of appropriate animal or cellular models, podocyte damage in Fabry's disease could not be directly studied yet. As murine models are insufficient, a human model is needed. Here, we developed a human podocyte model of Fabry's disease by combining RNA interference technology with lentiviral transduction of human podocytes. Knockdown of alpha-galactosidase A expression resulted in diminished enzymatic activity and slowly progressive accumulation of intracellular Gb3. Interestingly, these changes were accompanied by an increase in autophagosomes as indicated by an increased abundance of LC3-II and a loss of mTOR kinase activity, a negative regulator of the autophagic machinery. These data suggest that dysregulated autophagy in alpha-galactosidase A-deficient podocytes may be the result of deficient mTOR kinase activity. This finding links the lysosomal enzymatic defect in Fabry's disease to deregulated autophagy pathways and provides a promising new direction for further studies on the pathomechanism of glomerular injury in Fabry patients. |*Models, Biological[MESH] |Autophagy/*physiology[MESH] |DNA Primers/genetics[MESH] |Fabry Disease/*physiopathology[MESH] |Fluorescent Antibody Technique[MESH] |Gene Knockdown Techniques[MESH] |HEK293 Cells[MESH] |Humans[MESH] |In Situ Nick-End Labeling[MESH] |Luciferases[MESH] |Macrolides[MESH] |Male[MESH] |Podocytes/metabolism/*pathology[MESH] |RNA Interference[MESH] |Real-Time Polymerase Chain Reaction[MESH] |Sirolimus[MESH] |TOR Serine-Threonine Kinases/metabolism[MESH] |Trihexosylceramides/*metabolism[MESH]Dysregulated autophagy contributes to podocyte damage in Fabry s disea(epmc).pdf DeepDyve Pubget Overpricing