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High Glucose Stimulates Angiotensinogen Gene Expression and Cell Hypertrophy via Activation of the Hexosamine Biosynthesis Pathway in Rat Kidney Proximal Tubular Cells
- Source :
- Endocrinology. 144:4338-4349
- Publication Year :
- 2003
- Publisher :
- The Endocrine Society, 2003.
-
Abstract
- The present study investigated whether activation of the hexosamine biosynthesis pathway might mediate at least in part the high glucose effect on angiotensinogen (ANG) gene expression and immortalized renal proximal tubular cell (IRPTC) hypertrophy. IRPTC were cultured in monolayer. ANG, renin, and β-actin mRNA expression were determined by specific RT-PCR assays. Phosphorylation of p38 MAPK, activating transcription factor-2 (ATF-2), and cAMP-responsive element-binding protein (CREB) was determined by Western blot analysis. Cell hypertrophy was assessed by flow cytometry, intracellular p27kip1 protein levels, and [3H]leucine incorporation into proteins. Glucosamine stimulated ANG and renin mRNA expression and enhanced p38 MAPK, ATF-2, and CREB phosphorylation in normal glucose (5 mm) medium. Azaserine and 6-diazo-5-oxo-l-norleucine (inhibitors of glutamine: fructose-6-phosphate amino transferase enzyme) blocked the stimulatory effect of high glucose, but not that of glucosamine, on ANG gene expression in IRPTCs. SB 203580 (a specific p38 MAPK inhibitor) attenuated glucosamine action on ANG gene expression as well as p38 MAPK and ATF-2 phosphorylation, but not that of CREB. GF 109203X and calphostin C (inhibitors of protein kinase C) blocked the effect of glucosamine on ANG gene expression and CREB phosphorylation, but had no impact on p38 MAPK and ATF-2 phosphorylation. Finally, both glucosamine and high glucose induced IRPTC hypertrophy. The hypertrophic effect of glucosamine was blocked in the presence of GF 109203X, but not azaserine and SB 203580. In contrast, the hypertrophic effect of high glucose was blocked in the presence of azaserine and GF 109203X, but not SB203580. Our studies demonstrate that the stimulatory effect of high glucose on ANG gene expression and IRPTC hypertrophy may be mediated at least in part via activation of hexosamine biosynthesis pathway signaling.
- Subjects :
- medicine.medical_specialty
SB 203580
Diazooxonorleucine
Angiotensinogen
Gene Expression
CREB
p38 Mitogen-Activated Protein Kinases
Kidney Tubules, Proximal
chemistry.chemical_compound
Endocrinology
Glucosamine
Internal medicine
Gene expression
medicine
Animals
Azaserine
RNA, Messenger
Phosphorylation
Cyclic AMP Response Element-Binding Protein
Cell Line, Transformed
Activating Transcription Factor 2
Dose-Response Relationship, Drug
biology
Hexosamines
Hypertrophy
Activating transcription factor 2
Rats
Glucose
Calphostin C
chemistry
biology.protein
Mitogen-Activated Protein Kinases
Transcription Factors
medicine.drug
Subjects
Details
- ISSN :
- 19457170 and 00137227
- Volume :
- 144
- Database :
- OpenAIRE
- Journal :
- Endocrinology
- Accession number :
- edsair.doi.dedup.....415e632cffddba19f162300f5a97d28f
- Full Text :
- https://doi.org/10.1210/en.2003-0220