Wang Yuhong, Sun Zhongjie
Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, 940 S.L. Young Blvd., Oklahoma City, OK 73126-0901, USA.
Hypertension. 2009 Oct;54(4):810-7. doi: 10.1161/HYPERTENSIONAHA.109.134320. Epub 2009 Jul 27.
Klotho is a recently discovered antiaging gene. The objective of this study was to test the hypothesis that klotho gene delivery attenuates the progression of spontaneous hypertension and renal damage in spontaneous hypertensive rats (SHRs). An adeno-associated virus (AAV) carrying mouse klotho full-length cDNA (AAV.mKL) was constructed for in vivo expression of klotho. Four groups of male SHRs and 1 group of sex- and age-matched Wistar-Kyoto rats (5 rats per group) were used. Blood pressure was measured twice in all of the animals before gene delivery. Four groups of SHRs received an IV injection of AAV.mKL, AAV.LacZ, AAV.GFP, and PBS, respectively. The Wistar-Kyoto group received PBS and served as a control. AAV.mKL stopped the further increase in blood pressure in SHRs, whereas blood pressures continued to increase in other SHR groups. One single dose of AAV.mKL prevented the progression of spontaneous hypertension for at least 12 weeks (length of the study). Klotho expression and production were suppressed in SHRs, which were reverted by AAV.mKL. AAV.mKL increased plasma interleukin 10 levels but decreased Nox2 expression, NADPH oxidase activity, and superoxide production in kidneys and aortas in SHRs. AAV.mKL abolished renal tubular atrophy and dilation, tubular deposition of proteinaceous material, glomerular collapse, and collagen deposition seen in SHRs, indicating that klotho gene delivery attenuated renal damage. Therefore, the suppressed klotho expression may play a role in the progression of spontaneous hypertension and renal damage in SHRs. AAV delivery of klotho may offer a new approach for the long-term control of hypertension and for renoprotection.
klotho是最近发现的一种抗衰老基因。本研究的目的是验证以下假设：在自发性高血压大鼠（SHRs）中，递送klotho基因可减缓自发性高血压的进展以及肾脏损伤。构建了携带小鼠klotho全长cDNA的腺相关病毒（AAV）（AAV.mKL）用于在体内表达klotho。使用了四组雄性SHRs和一组性别及年龄匹配的Wistar-Kyoto大鼠（每组5只大鼠）。在基因递送前对所有动物测量两次血压。四组SHRs分别接受静脉注射AAV.mKL、AAV.LacZ、AAV.GFP和PBS。Wistar-Kyoto组接受PBS并作为对照。AAV.mKL阻止了SHRs血压的进一步升高，而其他SHR组的血压持续升高。单次注射AAV.mKL可预防自发性高血压的进展至少12周（研究时长）。SHRs中klotho的表达和产生受到抑制，而AAV.mKL可使其恢复。AAV.mKL增加了SHRs血浆白细胞介素10水平，但降低了肾脏和主动脉中Nox2的表达、NADPH氧化酶活性以及超氧化物的产生。AAV.mKL消除了SHRs中出现的肾小管萎缩和扩张、蛋白质物质的肾小管沉积、肾小球塌陷以及胶原沉积，表明递送klotho基因可减轻肾脏损伤。因此，klotho表达受抑制可能在SHRs自发性高血压和肾脏损伤的进展中起作用。通过AAV递送klotho可能为高血压的长期控制和肾脏保护提供一种新方法。
