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首页> 外文期刊>American Journal of Physiology >Attenuation of accelerated renal cystogenesis in Pkdl mice by renin-angiotensin system blockade
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Attenuation of accelerated renal cystogenesis in Pkdl mice by renin-angiotensin system blockade

机译：肾素 - 血管紧张素系统封锁PKDL小鼠加速肾囊泡的衰减

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The intrarenal renin angio-tensin system (RAS) is activated in polycystic kidney disease. We have recently shown in the Pkdl mouse that Gen 2 antisense oligo-nucleotide (ASO), which suppresses angiotensinogen (Agt) synthesis, is efficacious in slowing kidney cyst formation compared with lisin-opril. The aim of this current study was to determine 7) if unilateral nephrectomy accelerates cystogenesis in Pkdl mice (as previously shown in cilia knockout mice) and 2) whether Agt ASO can slow the progression in this accelerated cystic mouse model. Adult Pkdl conditional floxed allele mice expressing cre were administered ta-moxifen, resulting in global knockout of Pkdl. Three weeks after tamoxifen injection, mice underwent left unilateral nephrectomy. Mice were then treated with Agt ASO (75 mg/kg per week) or aliskiren (20 mg/kg per day)+Agt ASO or control for 8 wk. Unilateral nephrectomy accelerated kidney cyst formation compared with non-nephrectomized mice. Both Agt ASO and Aliskiren+Agt ASO treatments significantly reduced plasma and urinary Agt levels. Blood pressure was lowest in Aliskiren+Agt ASO mice among all treatment groups, and the control group had the highest blood pressure. All mice developed significant kidney cysts at 8 wk after nephrectomy, but Agl ASO and Aliskiren+Agt ASO groups had fewer kidney cysts than controls. Renal pAkt, pS6 levels, and apoptosis were significantly suppressed in those receiving Agt ASO compared with controls. These results indicate that suppressing Agt using an ASO slowed the progression of accelerated cystic kidney disease induced by unilateral nephrectomy in Pkdl mice by suppressing intrarenal RAS, mammalian target of rapamycin pathway, and cell proliferation.
机译：Intrarenal renin血管 - 泰素系统（RAS）在多囊肾疾病中激活。我们最近在PKDL鼠标中显示，抑制血管紧张素（AGT）合成的Gen 2反义寡核苷酸（ASO），与Lisin-Opril相比，肾脏囊肿形成的较慢性。该目前研究的目的是确定7）如果单侧肾切除术在PKDL小鼠中加速囊肠（如前所未有的玉米敲除小鼠）和2）是否可以减缓该加速囊性小鼠模型中的进展慢。表达CRE的成人PKDL条件浮动等位基因小鼠TA-Moxifen，导致PKDL的全局敲除。三莫昔芬注射液后三周，小鼠接受了单侧肾切除术。然后用AgT Aso（每周75mg / kg）或aliskiren（每天20mg / kg）+ agt aso或对照治疗小鼠或对照8 wk。单侧肾切除术加速肾囊肿形成与非肾切除小鼠相比。 AGT ASO和Aliskiren + AGT ASO治疗均显着降低了血浆和泌尿期患者水平。在所有治疗组中，Aliskiren + Agt ASO小鼠中血压最低，对照组具有最高的血压。所有小鼠在肾切除术后8周发出显着的肾脏囊肿，但AGL ASO和Aliskiren + AgT ASO组的肾脏囊肿比对照较少。在接受AGT Aso的那些与对照相比，肾脏PAKT，PS6水平和细胞凋亡受到显着抑制。这些结果表明，使用ASO抑制AGT通过抑制鼻部RA，哺乳动物途径和细胞增殖的哺乳动物靶标，抑制了PKDL小鼠中的单侧肾切除术诱导的加速囊性肾病的进展。

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