Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice
Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice
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DOI：
10.1681/asn.2006010029
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发表时间：
2006-07-01
影响因子：
13.6
通讯作者：
Inagami, Tadashi
中科院分区：
文献类型：
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作者：
Ichihara, Atsuhiro;Suzuki, Fumiaki;Inagami, Tadashi
阻断肾素-血管紧张素系统可减缓糖尿病肾病的进展，但不能消除糖尿病终末期肾病的发展。糖尿病时肾素原/活性肾素比值显著增加，糖尿病动物肾脏中前肾素与其受体结合可导致肾病，而不是常规的蛋白分解激活，提示血管紧张素II可能不是导致肾病的决定性因素。用链脲佐菌素诱导野生型小鼠和Angi1a受体基因缺陷小鼠糖尿病，观察糖尿病肾病的发生和发展，以确定AngiI非依赖性机制。此外，还比较了延长血管紧张素转换酶抑制时间和延长前肾素受体阻断时间对糖尿病血管紧张素Ⅱ1a受体基因缺陷小鼠肾病的预防作用。糖尿病大鼠肾脏血管紧张素转换酶(Ang11)水平虽无明显变化，但只有用前肾素短肽阻断前肾素受体，才能完全消除丝裂原活化蛋白激酶(MAPK)的激活和肾脏病变。这些结果表明，MAPK激活信号导致糖尿病肾病，而不是肾素-血管紧张素系统在肾小球中的其他激活机制。不仅是血管紧张素转换酶，而且受体相关的原肾素激活的MAPK在糖尿病肾病中起着关键作用。
Blockade of the renin-angiotensin system slows the progression of diabetic nephropathy but fails to abolish the development of end-stage nephropathy of diabetes. The prorenin-to-active renin ratio significantly increases in diabetes, and prorenin binding to its receptor in diabetic animal kidney induces the nephropathy without its conventional proteolytic activation, suggesting that angiotensin II (AngII) may not be the decisive factor causing the nephropathy. For identification of an AngII-independent mechanism, diabetes was induced in wild-type mice and AngIl type 1a receptor gene-deficient mice by streptozotocin treatment, and their development and progression of diabetic nephropathy were assessed. In addition, prolonged inhibition of angiotensin-converting enzyme and prolonged prorenin receptor blockade were compared for their efficacy in preventing the nephropathy that occurred in diabetic AngII type 1a receptor gene-deficient mice. Only the prorenin receptor blockade with a short peptide of prorenin practically abolished the increased mitogen-activated protein kinase (MAPK) activation and nephropathy despite unaltered increase in Angll in diabetic kidney. These results indicate that the MAPK activation signal leads to the diabetic nephropathy but not other renin-angiotensin system-activated mechanisms in the glomeruli. It is not only AngII but also intraglomerular activation of MAPK by the receptor-associated prorenin that plays a pivotal role in diabetic nephropathy.