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Pemt Deficiency Ameliorates Endoplasmic Reticulum Stress in Diabetic Nephropathy

Phosphatidylethanolamine N-methyltransferase (Pemt) catalyzes the methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) mainly in the liver. Under an obese state, the upregulation of Pemt induces endoplasmic reticulum (ER) stress by increasing the PC/PE ratio in the liver. We targ...

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Autores principales: Watanabe, Mayu, Nakatsuka, Atsuko, Murakami, Kazutoshi, Inoue, Kentaro, Terami, Takahiro, Higuchi, Chigusa, Katayama, Akihiro, Teshigawara, Sanae, Eguchi, Jun, Ogawa, Daisuke, Watanabe, Eijiro, Wada, Jun, Makino, Hirofumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3965443/
https://www.ncbi.nlm.nih.gov/pubmed/24667182
http://dx.doi.org/10.1371/journal.pone.0092647
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author Watanabe, Mayu
Nakatsuka, Atsuko
Murakami, Kazutoshi
Inoue, Kentaro
Terami, Takahiro
Higuchi, Chigusa
Katayama, Akihiro
Teshigawara, Sanae
Eguchi, Jun
Ogawa, Daisuke
Watanabe, Eijiro
Wada, Jun
Makino, Hirofumi
author_facet Watanabe, Mayu
Nakatsuka, Atsuko
Murakami, Kazutoshi
Inoue, Kentaro
Terami, Takahiro
Higuchi, Chigusa
Katayama, Akihiro
Teshigawara, Sanae
Eguchi, Jun
Ogawa, Daisuke
Watanabe, Eijiro
Wada, Jun
Makino, Hirofumi
author_sort Watanabe, Mayu
collection PubMed
description Phosphatidylethanolamine N-methyltransferase (Pemt) catalyzes the methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) mainly in the liver. Under an obese state, the upregulation of Pemt induces endoplasmic reticulum (ER) stress by increasing the PC/PE ratio in the liver. We targeted the Pemt gene in mice to explore the therapeutic impact of Pemt on the progression of diabetic nephropathy and diabetes, which was induced by the injection of streptozotocin (STZ). Although the blood glucose levels were similar in STZ-induced diabetic Pemt+/+ and Pemt−/−mice, the glomerular hypertrophy and albuminuria in Pemt−/− mice were significantly reduced. Pemt deficiency reduced the intraglomerular F4/80-positive macrophages, hydroethidine fluorescence, tubulointerstitial fibrosis and tubular atrophy. The expression of glucose-regulated protein-78 (GRP78) was enriched in the renal tubular cells in STZ-induced diabetic mice, and this was ameliorated by Pemt deficiency. In mProx24 renal proximal tubular cells, the treatment with ER-stress inducers, tunicamycin and thapsigargin, increased the expression of GRP78, which was reduced by transfection of a shRNA lentivirus for Pemt (shRNA-Pemt). The number of apoptotic cells in the renal tubules was significantly reduced in Pemt−/− diabetic mice, and shRNA-Pemt upregulated the phosphorylation of Akt and decreased the cleavage of caspase 3 and 7 in mProx24 cells. Taken together, these findings indicate that the inhibition of Pemt activity ameliorates the ER stress associated with diabetic nephropathy in a model of type 1 diabetes and corrects the functions of the three major pathways downstream of ER stress, i.e. oxidative stress, inflammation and apoptosis.
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spelling pubmed-39654432014-03-27 Pemt Deficiency Ameliorates Endoplasmic Reticulum Stress in Diabetic Nephropathy Watanabe, Mayu Nakatsuka, Atsuko Murakami, Kazutoshi Inoue, Kentaro Terami, Takahiro Higuchi, Chigusa Katayama, Akihiro Teshigawara, Sanae Eguchi, Jun Ogawa, Daisuke Watanabe, Eijiro Wada, Jun Makino, Hirofumi PLoS One Research Article Phosphatidylethanolamine N-methyltransferase (Pemt) catalyzes the methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) mainly in the liver. Under an obese state, the upregulation of Pemt induces endoplasmic reticulum (ER) stress by increasing the PC/PE ratio in the liver. We targeted the Pemt gene in mice to explore the therapeutic impact of Pemt on the progression of diabetic nephropathy and diabetes, which was induced by the injection of streptozotocin (STZ). Although the blood glucose levels were similar in STZ-induced diabetic Pemt+/+ and Pemt−/−mice, the glomerular hypertrophy and albuminuria in Pemt−/− mice were significantly reduced. Pemt deficiency reduced the intraglomerular F4/80-positive macrophages, hydroethidine fluorescence, tubulointerstitial fibrosis and tubular atrophy. The expression of glucose-regulated protein-78 (GRP78) was enriched in the renal tubular cells in STZ-induced diabetic mice, and this was ameliorated by Pemt deficiency. In mProx24 renal proximal tubular cells, the treatment with ER-stress inducers, tunicamycin and thapsigargin, increased the expression of GRP78, which was reduced by transfection of a shRNA lentivirus for Pemt (shRNA-Pemt). The number of apoptotic cells in the renal tubules was significantly reduced in Pemt−/− diabetic mice, and shRNA-Pemt upregulated the phosphorylation of Akt and decreased the cleavage of caspase 3 and 7 in mProx24 cells. Taken together, these findings indicate that the inhibition of Pemt activity ameliorates the ER stress associated with diabetic nephropathy in a model of type 1 diabetes and corrects the functions of the three major pathways downstream of ER stress, i.e. oxidative stress, inflammation and apoptosis. Public Library of Science 2014-03-25 /pmc/articles/PMC3965443/ /pubmed/24667182 http://dx.doi.org/10.1371/journal.pone.0092647 Text en © 2014 Watanabe et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Watanabe, Mayu
Nakatsuka, Atsuko
Murakami, Kazutoshi
Inoue, Kentaro
Terami, Takahiro
Higuchi, Chigusa
Katayama, Akihiro
Teshigawara, Sanae
Eguchi, Jun
Ogawa, Daisuke
Watanabe, Eijiro
Wada, Jun
Makino, Hirofumi
Pemt Deficiency Ameliorates Endoplasmic Reticulum Stress in Diabetic Nephropathy
title Pemt Deficiency Ameliorates Endoplasmic Reticulum Stress in Diabetic Nephropathy
title_full Pemt Deficiency Ameliorates Endoplasmic Reticulum Stress in Diabetic Nephropathy
title_fullStr Pemt Deficiency Ameliorates Endoplasmic Reticulum Stress in Diabetic Nephropathy
title_full_unstemmed Pemt Deficiency Ameliorates Endoplasmic Reticulum Stress in Diabetic Nephropathy
title_short Pemt Deficiency Ameliorates Endoplasmic Reticulum Stress in Diabetic Nephropathy
title_sort pemt deficiency ameliorates endoplasmic reticulum stress in diabetic nephropathy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3965443/
https://www.ncbi.nlm.nih.gov/pubmed/24667182
http://dx.doi.org/10.1371/journal.pone.0092647
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