Regression of glomerulosclerosis with high-dose angiotensin inhibition is linked to decreased plasminogen activator inhibitor-1
Regression of glomerulosclerosis with high-dose angiotensin inhibition is linked to decreased plasminogen activator inhibitor-1
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DOI：
10.1681/asn.2004060492
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发表时间：
2005-04-01
影响因子：
13.6
通讯作者：
Fogo, AB
中科院分区：
文献类型：
--
作者：
Ma, LJ;Nakamura, S;Fogo, AB
研究了血管紧张素11 1型受体拮抗剂（AT1RA）和/或血管紧张素1转换酶抑制剂（ACEI）对现有肾小球硬化的潜在作用和可能的机制。成年雄性Sprague Dawley大鼠行5/6肾切除术（Nx）。8周后通过肾活检评估肾小球硬化，并将大鼠分为活检硬化程度相同的组，在接下来的4周内进行治疗，直到12周时死亡：对照组，无进一步治疗（CONT），高剂量AT1RA，高剂量ACEI，以及不同的AT1RA+ACEI组合。5/6 Nx诱导的高血压和蛋白尿，除高剂量ACEI表现持续性蛋白尿外，其余各组均显著降低。高剂量ATIRA和ACEI显著降低硬化症的进展，AT1RA组从活检到尸检的硬化症平均减少-2.3%，而CONT组增加194% （P < 0.0001）。在接受at1ra治疗的大鼠和接受acei治疗的大鼠中，62%的大鼠和57%的大鼠在死亡时肾小球硬化消退，病变程度比活检时要轻。相比之下，联合组只有17%到33%的大鼠出现了退化。或者，这些数据可能反映了进展的停止，因为一些组有较高的血压和蛋白尿。然而，这种潜在的混杂效应并不能否定在这些大鼠中实现硬化消退的作用。回归不能用tgf - β 1和基质金属蛋白酶-2和-9 mRNA的变化来解释，但与金属蛋白酶-1和纤溶酶原激活物抑制剂-1的组织抑制剂减少有关。因此，血管紧张素抑制在一定程度上通过对基质调节的作用介导了神经退化。
The potential and possible mechanisms for regression of existing glomerulosclerosis by angiotensin 11 type 1 receptor antagonist (AT1RA) and/or angiotensin I converting enzyme inhibitor (ACEI) were investigated. Adult male Sprague Dawley rats underwent 5/6 nephrectomy (Nx). Glomerulosclerosis was assessed by renal biopsy 8 wk later, and rats were divided into groups with equal biopsy sclerosis and treated for the next 4 wk until they were killed at 12 wk as follows: Control with no further treatment (CONT), high-dose AT1RA, high-dose ACEI, and varying AT1RA+ACEI combinations. Hypertension and proteinuria induced by 5/6 Nx were significantly decreased by all treatments, except high-dose ACEI, which showed persistent proteinuria. High-dose ATIRA and ACEI markedly decreased progression of sclerosis, with -2.3% average decrease in sclerosis from biopsy to autopsy in AT1RA versus 194% increase in CONT (P < 0.0001). Glomerulosclerosis regressed, with less severe lesions at the time when the rats were killed than at biopsy in 62% of AT1RA-treated and 57% of ACEI-treated rats. In contrast, only 17 to 33% of rats in combination groups had regression. Alternatively, these data might be viewed as reflecting halting of progression, as some groups had higher BP and proteinuria. However, this potential confounding effect does not negate the effects to achieve regression of sclerosis in these rats. Regression was not explained by changes in mRNA of TGF-beta 1 and matrix metalloproteinase-2 and -9 but was linked to decreased tissue inhibitor of metalloproteinase-1 and plasminogen activator inhibitor-1. It is concluded that angiotensin inhibition mediates regression in part by effects on matrix modulation.