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Hyperglycaemia-induced intrarenal RAS activation: the contribution of metabolic pathways

Departments of Medicine and Radiology, Harvard Medical School and Brigham and Women's Hospital, 75 Francis Street, Boston, MA, USA, mlansang@ partners.org

Suzette Y Osei

Departments of Medicine and Radiology, Harvard Medical School and Brigham and Women's Hospital, 75 Francis Street, Boston, MA, USA

Caroline Coletti

Departments of Medicine and Radiology, Harvard Medical School and Brigham and Women's Hospital, 75 Francis Street, Boston, MA, USA

Janelle Krupinski

Departments of Medicine and Radiology, Harvard Medical School and Brigham and Women's Hospital, 75 Francis Street, Boston, MA, USA

Norman K Hollenberg

Departments of Medicine and Radiology, Harvard Medical School and Brigham and Women's Hospital, 75 Francis Street, Boston, MA, USA

Hyperglycaemia-induced activation of the renin-angiotensin system (RAS) has been observed in normal and diabetic humans. Our main objective was to determine whether the mechanism involved a physical or metabolic effect of glucose. First, Sprague-Dawley rats of the CD strain were given sequential intravenous (i.v.) doses of 0.01, 0.1, 1.0, and 3.0 mg/kg candesartan 30 minutes apart, in the presence of a continuous i.v. infusion of dextrose 20% in water (D20W). The 0.1 mg/kg dose produced a maximal renal blood flow (RBF) response and was used thereafter. Another set of animals then received an infusion of either normal saline (NS), dextrose 5% in water (D5W) or dextrose 20% in water (D20W) for 2 hours, followed by candesartan 0.1 mg/kg i.v. Finally, the response to candesartan 0.1 mg/kg i.v. during D20W infusion was compared with that during infusion of 2-deoxyglucose (2DG), a glucose analogue that competitively inhibits the glycolytic enzyme, hexokinase. RBF (electromagnetic flowmeter), blood pressure (BP), blood glucose, and urine glucose were monitored. There was no significant RBF response to candesartan on either NS (6.01±0.48 to 6.20±0.49 ml/minute/g kidney; p=0.216) or D5W (7.63±1.20 to 7.58±1.39 ml/minute/g kidney; p=0.965), whereas there was a significant response to D20W (6.64±0.59 to 7.46±0.67 ml/minute/g kidney; p=0.002). The RBF response was significantly enhanced by D20W compared with 2DG (change in RBF: 0.82±0.22 vs. -0.04±0.26; p=0.05), despite similar BP, blood glucose, and urine glucose. Glucose acts, at least in part, through intracellular utilisation to induce RAS activation, as manifested by an enhanced renal vascular response to an angiotensin II antagonist.

Key Words: candesartan • 2-deoxyglucose • glucose

Journal of Renin-Angiotensin-Aldosterone System, Vol. 3, No. 1, 19-23 (2002)
DOI: 10.3317/jraas.2002.003


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