Reduced glomerular angiotensin II receptor density in diabetes mellitus in the rat: time course and mechanism.

Glomerular angiotensin II receptors are reduced in number in early diabetes 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 less than 0.001) and a fall in plasma insulin (control, 53.1 +/- 5.7; diabetic, 35.6 +/- 4.0 microIU/ml; P less than 0.05). At 24 h glomerular angiotensin II receptor density was decreased by 26.5% in diabetic rats (control, 75.5 +/- 9.6 X 10(6); diabetic, 55.5 +/- 8.3 X 10(6) receptors/glomerulus; P less than 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 less than 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 X 10(6); diabetic, 18.5 +/- 1.3 X 10(6) receptors/glomerulus; P less than 0.05); and angiotensin-converting enzyme inhibition with enalapril caused receptor up-regulation, but the differences persisted (control, 105.5 +/- 21.2 X 10(6); diabetic, 67.1 +/- 3.0 X 10(6) receptors/glomerulus; P less than 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 less than 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.