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High Levels of Glucose Stimulate Angiotensinogen Gene Expression Via the P38 Mitogen-Activated Protein Kinase Pathway in Rat Kidney Proximal Tubular Cells¹

University of Montréal, Maisonneuve-Rosemont Hospital Research Center (S.-L.Z., X.C., J.G.F., J.S.D.C.), Montréal, Québec, Canada H1T 2M4; and Harvard Medical School, Pediatric Nephrology Unit, Massachusetts General Hospital (S.-S.T., J.R.I.), Boston, Massachusetts 02114-3117

Address all correspondence and requests for reprints to: Dr. John S. D. Chan, University of Montréal, Centre Hospitalier de l’Université de Montréal, Hôtel-Dieu Hospital, Pavillon Masson, 3850 St. Urbain Street, Montréal, Québec, Canada H2W 1T8. E-mail: john.chan{at}umontreal.ca

The present studies investigated whether the effect of high levels of glucose on angiotensinogen (ANG) secretion and gene expression in kidney proximal tubular cells is mediated at least in part via the activation of p38 mitogen-activated protein kinase (p38 MAPK). Rat immortalized renal proximal tubular cells (IRPTCs) were cultured in monolayer. The levels of immunoreactive rat ANG (IR-rANG) secreted into the medium and the levels of cellular ANG messenger RNA were determined by a specific RIA for rat ANG and a RT-PCR assay, respectively. Phosphorylation of cellular p38 MAPK was determined by Western blot analysis using the Phospho Plus p38 MAPK antibody kit. High levels of glucose (i.e. 25 mM) and phorbol 12-myristate 13-acetate (PMA; 10^-7 M) increased the secretion of IR-rANG and cellular ANG messenger RNA as well as phosphorylation of p38 MAPK in IRPTCs. This stimulatory effect of high levels of glucose and PMA was blocked by SB 203580 (a specific inhibitor of p38 MAPK), but not by SB 202474 (a negative control of SB 203580). High levels of D-sorbitol or 2-deoxy-D-glucose (i.e. 35 mM) also stimulated the phosphorylation of p38 MAPK, but did not stimulate ANG secretion or gene expression. GF 109203X (an inhibitor of protein kinase C) blocked the stimulatory effect of high levels of glucose and PMA on ANG gene expression, whereas it did not block the effect of high levels of glucose, sorbitol, or 2-deoxy-D-glucose on p38 MAPK phosphorylation in IRPTCs. These studies demonstrate that the stimulatory effect of a high level of glucose (25 mM) on ANG gene expression in IRPTCS may be mediated at least in part via activation of p38 MAPK signal transduction pathway and is protein kinase C independent.