Pemt deficiency ameliorates endoplasmic reticulum stress in diabetic nephropathy

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

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Abstract

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.

Original languageEnglish
Article numbere92647
JournalPLoS One
Volume9
Issue number3
DOIs
Publication statusPublished - Mar 25 2014

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phosphatidylethanolamine N-methyltransferase
Phosphatidylethanolamine N-Methyltransferase
diabetic nephropathy
Endoplasmic Reticulum Stress
Diabetic Nephropathies
endoplasmic reticulum
Streptozocin
streptozotocin
Lentivirus
Medical problems
mice
Phosphatidylcholines
Kidney
Liver
Small Interfering RNA
phosphatidylethanolamines
phosphatidylcholines
Caspase 7
Tunicamycin
Phosphorylation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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.

In: PLoS One, Vol. 9, No. 3, e92647, 25.03.2014.

Research output: Contribution to journalArticle

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. In: PLoS One. 2014 ; Vol. 9, No. 3.
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AU - Terami, Takahiro

AU - Higuchi, Chigusa

AU - Katayama, Akihiro

AU - Teshigawara, Sanae

AU - Eguchi, Jun

AU - Ogawa, Daisuke

AU - Watanabe, Eijiro

AU - Wada, Jun

AU - Makino, Hirofumi

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