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Université de Montréal Centre Hospitalier de l’Université de Montréal-Hôtel Dieu Centre de Recherche Pavillon Masson (T.-J.H., P.F., S.-L.Z., P.H., J.S.D.C.), Montréal, Québec, Canada H2W 1T8; Maisonneuve-Rosemont Hospital, Research Center (J.G.F.), Montréal, Québec, Canada H1T 2M4; Harvard Medical School, Massachusetts General Hospital, Pediatric Nephrology Unit (S.-S.T., J.R.I.), Boston, Massachusetts 02114-3117; and Mount Sinai Hospital, Department of Medicine, University of Toronto (G.F.), Toronto, Ontario, Canada M5G 1X5
Address all correspondence and requests for reprints to: Dr. John S. D. Chan, Université de Montréal Centre Hospitalier de l’Université de Montréal-Hôtel Dieu Centre de Recherche Pavillon Masson, Montréal, Québec, Canada H2W 1T8. E-mail: john.chan{at}umontreal.ca.
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 ß-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.
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