Role of endothelin-1 in the renal handling of salt in early Type 1 diabetes mellitus
Culshaw, Geoffrey Jonathan
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Tight control of blood glucose and blood pressure (BP) reduces cardiovascular risk in early Type 1 diabetes mellitus (T1DM). Increased BP normally increases renal medullary perfusion and sodium excretion. This is called acute pressure natriuresis. Inadequate acute pressure natriuresis disrupts circadian regulation of BP, which predicts hypertension. The peptide, endothelin-1 (ET-1), regulates BP via ETA and ETB receptors. ETA receptor antagonists reduce BP and restore its circadian rhythm. Two hypotheses were investigated. First, that acute pressure natriuresis is impaired in early T1DM, prior to established nephropathy, and this is associated with elevated BP. Second, that the mechanism is an ETA receptor-mediated blunting of medullary perfusion which can be reversed with insulin and ETA receptor antagonism. Experimental acute pressure natriuresis was induced in young, early T1DM (2-3 weeks post streptozotocin) Sprague Dawley rats and healthy controls. Despite maintaining glomerular filtration rate, early T1DM suppressed urinary flow (UV, 22.9±2.9 v. 93.7±11.1μl/min/gkw) and sodium excretion (UNaV, 3.2±0.7 v. 22.7±3.3μmol/min/gkw) rates by >80%, and reduced gradients of pressure diuresis (linear, 1.9 to 0.3) and natriuresis (non-linear k, 0.05 to 0.01) curves. Insulin treatment lowered blood glucose (16.8±1.8 to 9.3±0.6mmol/l) and restored gradients of the responses. Tissue and urine analyses did not suggest structural nephropathy. In early T1DM rats, changes in BP on radiotelemetry were consistent with impaired circadian regulation of BP and precursors of hypertension: 24–hour diastolic BP rose (92.3±0.4 to 97.1±0.5mmHg), and the circadian dip in diastolic BP fell (6±1 to 2±1%). Atrasentan (ETA receptor antagonist, 5mg/kg/day orally) reduced diastolic dipping in early T1DM (3±1 to 1±1%) while additional ETB receptor antagonism (A-192621, 10mg/kg/day orally) reversed this, suggesting that ETA, and not ETB receptors, mediate impairment of acute pressure natriuresis. To address this, renal blood flow was measured during experimental acute pressure natriuresis and ET receptor antagonism. Early T1DM suppressed the normal rise in medullary perfusion (flux, 227.2±26.7 v. 115.4±10.3%) by ~90%. Suppressed medullary flux was unaffected by insulin (112.2±6.8%), despite restoration of UV and UNaV. In controls, atrasentan reduced UV (15.7±4.9 v. 38.6±6.2μl/min/gkw), UNaV (1.7±0.5 v. 16.7±1.4μmol/min/gkw), FENa (3.4±1.4 v. 15.0±2.4%) and medullary flux (122.2±26.7%) by 60 to 90% of control values, while A-192621 increased UNaV (26.6±6.9μmol/min/gkw) and FENa (21.6±3.4%), but not medullary flux, by ~50%. ET receptor antagonism did not modify early T1DM+/-insulin effects. Diabetic status had no effect on renal ET-1 and ET receptor expression. These results support the first hypothesis but disprove the second. Early T1DM blunts medullary perfusion and acute pressure natriuresis, and increases diastolic BP. Insulin restores natriuresis but not medullary flow. Therefore, targeting medullary perfusion may reduce cardiovascular risk in early T1DM, but this is not achievable with selective ETA receptor antagonists. Novel natriuretic (ETA) and anti-natriuretic (ETB) roles for ET receptors, which are not apparent in early T1DM during severe, experimental rises in BP, appear to contribute to daily regulation of BP, and may preclude the use of selective ETA receptor antagonists in T1DM prior to nephropathy.