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Pemt deficiency ameliorates endoplasmic reticulum stress in diabetic nephropathy.
- Source :
-
PloS one [PLoS One] 2014 Mar 25; Vol. 9 (3), pp. e92647. Date of Electronic Publication: 2014 Mar 25 (Print Publication: 2014). - Publication Year :
- 2014
-
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.
- Subjects :
- Animals
Apoptosis genetics
Diabetes Mellitus, Experimental genetics
Diabetes Mellitus, Experimental pathology
Diabetes Mellitus, Type 1 genetics
Diabetes Mellitus, Type 1 pathology
Diabetic Nephropathies genetics
Diabetic Nephropathies pathology
Endoplasmic Reticulum Chaperone BiP
Gene Expression Regulation genetics
Heat-Shock Proteins biosynthesis
Heat-Shock Proteins genetics
Inflammation genetics
Inflammation metabolism
Inflammation pathology
Kidney Tubules, Proximal pathology
Mice
Mice, Knockout
Oxidative Stress genetics
Phosphatidylethanolamine N-Methyltransferase genetics
Proto-Oncogene Proteins c-akt genetics
Proto-Oncogene Proteins c-akt metabolism
Diabetes Mellitus, Experimental metabolism
Diabetes Mellitus, Type 1 metabolism
Diabetic Nephropathies metabolism
Endoplasmic Reticulum Stress
Kidney Tubules, Proximal metabolism
Phosphatidylethanolamine N-Methyltransferase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 9
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 24667182
- Full Text :
- https://doi.org/10.1371/journal.pone.0092647