Reduced Glomerular Angiotensin II Receptor Density in Diabetes Mellitus in the Rat: Time Course and Mechanism*

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Abstract
Glomerular angiotensin II receptors are reduced in number in early diabetus mellitus, which may contribute to hyperfiltration and glomerular injury. The time course and role of the renin-angiotensin-aldosterone system in the pathogenesis of the receptor abnormality were studied in male Sprague-Dawley rats made diabetic with streptozotocin (65 mg, iv). Glomerular angiotensin II receptors were measured by Scatchard analysis; insulin, renin activity, angiotensin II, and aldosterone were measured by RIA. Diabetes mellitus was documented at 24 h by a rise in plasma glucose (vehicle-injected control, 133 .+-. 4; diabetic 482 .+-. 22 mg/dl; P < 0.001) and a fall in plasma insulin (control, 53.1 .+-. 5.7; diabetic, 35.6 .+-. 4.0 .mu.IU/ml; P < 0.05). At 24 h glomerular angiotensin II receptor density was decreased by 26.5% in diabetic rats (control, 75.5 .+-. 9.6 .times. 106; diabetic, 55.5 .+-. 8.3 .times. 106 receptors/glomerulus; P < 0.01). Receptor occupancy could not explain the defect, because there was reduced binding in diabetic glomeruli after pretreatment with 3 M MgCl2, a maneuver that caused dissociation of previously bound hormone. There was a progressive return of the receptor density toward normal over the 60 days following induction of diabetes, with diabetic glomeruli measuring 22.7%, 14.8%, and 3.7% fewer receptors than age-matched controls at 11 days, 1 month, and 2 months, respectively (r = 0.99; n = 4; P < 0.01). Three lines of evidence suggested that reduced angiotensin II receptor density at 24 h was not due to down-regulation by angiotensin II: PRA and angiotensin II were identical in control and diabetic rats; angiotensin II infusion (50 ng/min) caused down-regulation in both control and diabetic rats, but the change in receptor density persisted (control, 33.6 .+-. 6.9 .times. 106; diabetic, 18.5 .+-. 1.3 .times. 106 receptors/glomerulus; P < 0.05); and angiotensin-converting enzyme inhibition with enalapril caused receptor up-regulation, but the differences persisted (control, 105.5 .+-. 21.2 .times. 106; diabetic, 67.1 .+-. 3.0 .times. 106 receptors/glomerulus; P < 0.05). Rats with chronic diabetes (7-60 days) had normal PRA and angiotensin II, but plasma aldosterone was elevated (control, 29.8 .+-. 3.3; diabetic, 68.6 .+-. 12.4 ng/dl; P < 0.005). The return of angiotensin II receptor density to normal levels in chronic diabetes may be the result of receptor up-regulation by increased plasma aldosterone rather than recovery of the underlying defect.