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...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3965443?pdf=render |
| _version_ | 1811282231089430528 |
|---|---|
| author | Mayu Watanabe Atsuko Nakatsuka Kazutoshi Murakami Kentaro Inoue Takahiro Terami Chigusa Higuchi Akihiro Katayama Sanae Teshigawara Jun Eguchi Daisuke Ogawa Eijiro Watanabe Jun Wada Hirofumi Makino |
| author_facet | Mayu Watanabe Atsuko Nakatsuka Kazutoshi Murakami Kentaro Inoue Takahiro Terami Chigusa Higuchi Akihiro Katayama Sanae Teshigawara Jun Eguchi Daisuke Ogawa Eijiro Watanabe Jun Wada Hirofumi Makino |
| author_sort | Mayu Watanabe |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-13T01:49:00Z |
| format | Article |
| id | doaj.art-df6726209c6a4bc7bf107f246391af25 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T01:49:00Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-df6726209c6a4bc7bf107f246391af252022-12-22T03:07:57ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0193e9264710.1371/journal.pone.0092647Pemt deficiency ameliorates endoplasmic reticulum stress in diabetic nephropathy.Mayu WatanabeAtsuko NakatsukaKazutoshi MurakamiKentaro InoueTakahiro TeramiChigusa HiguchiAkihiro KatayamaSanae TeshigawaraJun EguchiDaisuke OgawaEijiro WatanabeJun WadaHirofumi MakinoPhosphatidylethanolamine 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.http://europepmc.org/articles/PMC3965443?pdf=render |
| spellingShingle | Mayu Watanabe Atsuko Nakatsuka Kazutoshi Murakami Kentaro Inoue Takahiro Terami Chigusa Higuchi Akihiro Katayama Sanae Teshigawara Jun Eguchi Daisuke Ogawa Eijiro Watanabe Jun Wada Hirofumi Makino Pemt deficiency ameliorates endoplasmic reticulum stress in diabetic nephropathy. PLoS ONE |
| 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 |
| url | http://europepmc.org/articles/PMC3965443?pdf=render |
| work_keys_str_mv | AT mayuwatanabe pemtdeficiencyamelioratesendoplasmicreticulumstressindiabeticnephropathy AT atsukonakatsuka pemtdeficiencyamelioratesendoplasmicreticulumstressindiabeticnephropathy AT kazutoshimurakami pemtdeficiencyamelioratesendoplasmicreticulumstressindiabeticnephropathy AT kentaroinoue pemtdeficiencyamelioratesendoplasmicreticulumstressindiabeticnephropathy AT takahiroterami pemtdeficiencyamelioratesendoplasmicreticulumstressindiabeticnephropathy AT chigusahiguchi pemtdeficiencyamelioratesendoplasmicreticulumstressindiabeticnephropathy AT akihirokatayama pemtdeficiencyamelioratesendoplasmicreticulumstressindiabeticnephropathy AT sanaeteshigawara pemtdeficiencyamelioratesendoplasmicreticulumstressindiabeticnephropathy AT juneguchi pemtdeficiencyamelioratesendoplasmicreticulumstressindiabeticnephropathy AT daisukeogawa pemtdeficiencyamelioratesendoplasmicreticulumstressindiabeticnephropathy AT eijirowatanabe pemtdeficiencyamelioratesendoplasmicreticulumstressindiabeticnephropathy AT junwada pemtdeficiencyamelioratesendoplasmicreticulumstressindiabeticnephropathy AT hirofumimakino pemtdeficiencyamelioratesendoplasmicreticulumstressindiabeticnephropathy |