In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage
In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage
复制标题
DOI：
10.1161/01.hyp.0000013734.33441.ea
复制
发表时间：
2002-04-01
期刊：
影响因子：
8.3
通讯作者：
Nagai, R
中科院分区：
文献类型：
--
作者：
Mitani, H;Ishizaka, N;Nagai, R
Klotho基因最初是通过插入突变在小鼠身上鉴定出来的，它抑制了多种与衰老相关的表型的表达。该基因主要在肾脏中表达。最近的研究表明，在代谢性疾病的动物模型和慢性肾功能衰竭的人类中，肾Klotho基因的表达受到调节。然而，在一些疾病条件下，Klotho基因在肾脏中表达的调节机制和生理相关性还知之甚少。在本研究中，我们首先研究了血管紧张素H在调节肾脏klotho基因表达中的作用。长期输注血管紧张素11可在mRNA和蛋白水平下调肾Klotho基因的表达。这种血管紧张素II诱导的肾Klotho下调是一种血管紧张素I型受体依赖但不依赖升压的事件。部分大鼠在开始血管紧张素II输注前立即静脉注射携带Klotho基因的腺病毒(AdKlotho，3.3×10(10)个空斑形成单位)。这导致了Klotho蛋白在肝脏中的强烈诱导，在基因转移后14天仍可检测到Klotho蛋白，Ad-Klotho基因转移，而不是ad-LacZ基因转移，导致肌酐清除改善，尿蛋白排泄减少，组织学证实的血管紧张素II所致的肾小管间质损伤得到改善。我们的数据表明，Klotho基因的下调可能在血管紧张素II诱导的肾脏损伤的发生中起加重作用，并且Klotho基因的诱导可能在治疗血管紧张素II诱导的终末器官损伤方面具有治疗可能性。
The klotho gene, originally identified by insertional mutagenesis in mice, suppresses the expression of multiple aging-associated phenotypes. This gene is predominantly expressed in the kidney. Recent studies have shown that expression of renal klotho gene is regulated in animal models of metabolic diseases and in humans with chronic renal failure. However, little is known about the mechanisms and the physiological relevance of the regulation of the expression of the klotho gene in the kidney in some diseased conditions. In the present study, we first investigated the role of angiotensin H in the regulation of renal klotho gene expression. Long-term infusion of angiotensin 11 downregulated renal klotho gene expression at both the mRNA and protein levels. This angiotensin II-induced renal klotho downregulation was an angiotensin type I receptor-dependent but pressor-independent event. Adenovirus harboring mouse klotho gene (ad-klotho, 3.3 X 10(10) plaque forming units) was also intravenously administered immediately before starting angiotensin II infusion in some rats. This resulted in a robust induction of Klotho protein in the liver at day 4, which was still detectable 14 days after the gene transfer, Ad-klotho gene transfer, but not ad-lacZ gene transfer, caused an improvement of creatinine clearance, decrease in urinary protein excretion, and amelioration of histologically demonstrated tubulointerstitial damage induced by angiotensin II administration. Our data suggest that downregulation of the renal klotho gene may have an aggravative role in the development of renal damage induced by angiotensin II, and that induction of the klotho gene may have therapeutic possibilities in treating angiotensin II-induced end organ damage.