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Hyperglycaemia-induced intrarenal RAS activation: the contribution of metabolic pathways
M Cecilia Lansang
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
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Journal of Renin-Angiotensin-Aldosterone System, Vol. 3, No. 1,
19-23 (2002)
DOI: 10.3317/jraas.2002.003
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