Wilkes B M
Endocrinology. 1987 Apr;120(4):1291-8. doi: 10.1210/endo-120-4-1291.
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.
在糖尿病早期，肾小球血管紧张素II受体数量减少，这可能导致超滤和肾小球损伤。我们在经链脲佐菌素（65mg，静脉注射）诱导糖尿病的雄性Sprague-Dawley大鼠中，研究了肾素-血管紧张素-醛固酮系统在受体异常发病机制中的时间进程和作用。通过Scatchard分析测定肾小球血管紧张素II受体；通过放射免疫分析法测定胰岛素、肾素活性、血管紧张素II和醛固酮。糖尿病在24小时时通过血糖升高得以证实（注射溶媒的对照组，133±4；糖尿病组，482±22mg/dl；P<0.001）以及血浆胰岛素降低（对照组，53.1±5.7；糖尿病组，35.6±4.0μIU/ml；P<0.05）。在24小时时，糖尿病大鼠肾小球血管紧张素II受体密度降低了26.5%（对照组，75.5±9.6×10⁶；糖尿病组，55.5±8.3×10⁶受体/肾小球；P<0.01）。受体占有率无法解释该缺陷，因为在用3M MgCl₂预处理后，糖尿病肾小球中的结合减少，这一操作导致先前结合的激素解离。在糖尿病诱导后的60天内，受体密度逐渐恢复正常，糖尿病肾小球在11天、1个月和2个月时分别比年龄匹配的对照组少22.7%、14.8%和3.7%的受体（r = 0.99；n = 4；P<0.01）。三条证据表明，24小时时血管紧张素II受体密度降低并非由于血管紧张素II的下调：对照组和糖尿病大鼠的肾素活性和血管紧张素II相同；血管紧张素II输注（50ng/min）在对照组和糖尿病大鼠中均导致下调，但受体密度的变化持续存在（对照组，33.6±6.9×10⁶；糖尿病组，18.5±1.3×10⁶受体/肾小球；P<0.05）；依那普利抑制血管紧张素转换酶导致受体上调，但差异仍然存在（对照组，105.5±21.2×10⁶；糖尿病组，67.1±3.0×10⁶受体/肾小球；P<0.05）。患有慢性糖尿病（7 - 60天）的大鼠肾素活性和血管紧张素II正常，但血浆醛固酮升高（对照组，29.8±3.3；糖尿病组，68.6±12.4ng/dl；P<0.005）。慢性糖尿病中血管紧张素II受体密度恢复到正常水平可能是血浆醛固酮增加导致受体上调的结果，而非潜在缺陷的恢复。
