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Insulin Inhibits Dexamethasone Effect on Angiotensinogen Gene Expression and Induction of Hypertrophy in Rat Kidney Proximal Tubular Cells in High Glucose

Université de Montréal, Centre Hospitalier de l’Université de Montréal (S.-L.Z., X.C., C.-C.W., J.S.D.C.), Hôtel-Dieu Hospital, Research Center, Montréal, Québec H2W 1T8 Canada; Université de Montréal (J.G.F.), Maisonneuve-Rosemont Hospital, Research Center, Montréal, Québec, Canada, H1T 2M4; and Harvard Medical School (S.-S.T., J.R.I.), Massachusetts General Hospital, Pediatric Nephrology Unit, Boston, Massachusetts 02114-3117

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

The present studies investigated whether insulin inhibits the stimulatory effect of dexamethasone (DEX) on angiotensinogen (ANG) gene expression and induction of hypertrophy in rat immortalized renal proximal tubular cells (IRPTCs) in a high-glucose milieu. Rat IRPTCs were cultured in monolayer. ANG and ANG mRNA expression in IRPTCs were quantified by a specific RIA for rat ANG and by RT-PCR assay, respectively. A fusion gene containing the full length of the 5'-flanking region of the rat ANG gene linked to a chloramphenicol acetyl transferase reporter gene was introduced into IRPTCs. The level of fusion gene expression was determined by cellular chloramphenicol acetyl transferase enzymatic activity. Cellular hypertrophy was assessed by flow cytometry, cellular p27^Kip1 protein expression, and protein assay. Our results showed that high glucose (i.e. 25 mM) and DEX (10^-7 M) additively stimulated ANG gene expression and induced IRPTC hypertrophy. Insulin inhibited the effect of high glucose and DEX on these parameters. The inhibitory effect of insulin was reversed by PD 98059 (a MAPK inhibitor) but not by wortmannin (a phosphatidylinositol-3-kinase inhibitor). These results demonstrate that insulin is effective in blocking the stimulatory action of high glucose and DEX on ANG gene expression and induction of IRPTC hypertrophy, suggesting its important role in preventing local intrarenal renin-angiotensin system activation and renal proximal tubular cell hypertrophy induced by hyperglycemia and glucocorticoids in vivo.

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