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      Effect of Renin-Angiotensin System Blockade on the Expression of the Angiotensinogen Gene and Induction of Hypertrophy in Rat Kidney Proximal Tubular Cells

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          Studies have shown that high levels of glucose and angiotensin II (Ang II) stimulate hypertrophy and the expression of matrix protein genes in mouse proximal tubular cells in vitro. The present study tested the hypothesis that blockade of the renin-angiotensin system (RAS) inhibits the stimulatory effect of high levels of glucose on the expression of the renal angiotensinogen (ANG) gene and the formation of Ang II and subsequently attenuates the induction of hypertrophy in kidney proximal tubular cells. Immortalized rat proximal tubular cells (IRPTC) were cultured in monolayer. The levels of expression of rat ANG and ANG mRNA in the IRPTC were quantified by specific radioimmunoassays for rat ANG (RIA-rANG) and by a reverse-transcription polymerase chain reaction (RT-PCR) assay, respectively. Hypertrophy of IRPTC was analyzed by flow cytometry (FACScan) and cellular protein assay. Our studies showed that losartan (an Ang II (AT<sub>1</sub>)-receptor blocker), perindopril and captopril (inhibitors of angiotensin-converting enzyme) blocked the stimulatory effect of a high level of glucose (i.e. 25 m M) on the expression of the rat ANG gene and hypertrophy in IRPTC but not by the Ang II (AT<sub>2</sub>)-receptor blocker. Our studies indicate that the blockade of RAS is effective in inhibiting the stimulatory effect of hyperglycemia on the expression of the ANG gene and hypertrophy in IRPTC, supporting the notion that the local formation of intrarenal Ang II may play a role in the development of renal hypertrophy during early diabetes.

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          Synergistic effect of dexamethasone and isoproterenol on the expression of angiotensinogen in immortalized rat proximal tubular cells.

          To investigate whether the expression of angiotensinogen (ANG) in rat kidney proximal tubules is stimulated by dexamethasone and isoproterenol, immortalized rat proximal tubular cells (IRPTC) were cultured in a monolayer. Immunoreactive rat ANG (IR-rANG) in the culture medium was measured by a specific radioimmunoassay (RIA) for rANG. This RIA was developed by employing rabbit antiserum against the purified recombinant rat ANG (rANG). The purified rANG from plasma and the iodinated rANG were used as the hormone standard and tracer, respectively. The RIA is specific for rat ANG and it has no cross-reactivity with other pituitary hormone preparations or other rat plasma proteins. The sensitivity of detection of the RIA is approximately 2 ng of rANG. The levels of IR-rANG in the culture media of IRPTC ranged from 2 to 5 ng/ml/24 hr/10(6) cells. The addition of dexamethasone (10(-13) to 10(-5) M) stimulated the expression and secretion of rANG from IRPTC in a dose-dependent manner, whereas the addition of isoproterenol alone had no effect. However, a combination of both dexamethasone and isoproterenol synergistically stimulated the expression and secretion of rANG by IRPTC. The synergistic effect of dexamethasone and isoproterenol was blocked by the presence of RU 486 (a glucocorticoid receptor antagonist) or propranolol (beta-adrenoceptor blocker). These studies suggest that the addition of dexamethasone and isoproterenol acts synergistically to stimulate the expression and secretion of ANG protein in rat proximal tubules in vivo.

            Author and article information

            Nephron Exp Nephrol
            Cardiorenal Medicine
            S. Karger AG
            April 2001
            11 January 2001
            : 9
            : 2
            : 109-117
            aUniversity of Montreal, Maisonneuve-Rosemont Hospital Research Center, Montreal, Que., Canada; bHarvard Medical School, Massachusetts General Hospital, Pediatric Nephrology Unit, Boston, Mass., USA; cServier Amérique, Laval, Que., Canada
            52601 Exp Nephrol 2001;9:109–117
            © 2001 S. Karger AG, Basel

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            Page count
            Figures: 9, References: 27, Pages: 9
            Self URI (application/pdf): https://www.karger.com/Article/Pdf/52601
            Original Paper

            Cardiovascular Medicine, Nephrology

            Angiotensinogen, Hyperglycemia, Kidney and hypertrophy


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