Kumar Vikash, Wollner Clayton, Kurth Theresa, Bukowy John D, Cowley Allen W
From the Department of Physiology, Medical College of Wisconsin, Milwaukee.
Hypertension. 2017 Oct;70(4):813-821. doi: 10.1161/HYPERTENSIONAHA.117.09456. Epub 2017 Aug 21.
The goal of the present study was to explore the protective effects of mTORC1 (mammalian target of rapamycin complex 1) inhibition by rapamycin on salt-induced hypertension and kidney injury in Dahl salt-sensitive (SS) rats. We have previously demonstrated that HO is elevated in the kidneys of SS rats. The present study showed a significant upregulation of renal mTORC1 activity in the SS rats fed a 4.0% NaCl for 3 days. In addition, renal interstitial infusion of HO into salt-resistant Sprague Dawley rats for 3 days was also found to stimulate mTORC1 activity independent of a rise of arterial blood pressure. Together, these data indicate that the salt-induced increases of renal HO in SS rats activated the mTORC1 pathway. Daily administration of rapamycin (IP, 1.5 mg/kg per day) for 21 days reduced salt-induced hypertension from 176.0±9.0 to 153.0±12.0 mm Hg in SS rats but had no effect on blood pressure salt sensitivity in Sprague Dawley treated rats. Compared with vehicle, rapamycin reduced albumin excretion rate in SS rats from 190.0±35.0 to 37.0±5.0 mg/d and reduced the renal infiltration of T lymphocytes (CD3) and macrophages (ED1) in the cortex and medulla. Renal hypertrophy and cell proliferation were also reduced in rapamycin-treated SS rats. We conclude that enhancement of intrarenal HO with a 4.0% NaCl diet stimulates the mTORC1 pathway that is necessary for the full development of the salt-induced hypertension and kidney injury in the SS rat.
本研究的目的是探讨雷帕霉素抑制哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）对Dahl盐敏感（SS）大鼠盐诱导的高血压和肾损伤的保护作用。我们之前已经证明，SS大鼠肾脏中的血红素加氧酶（HO）水平升高。本研究表明，给SS大鼠喂食4.0%氯化钠3天，其肾脏mTORC1活性显著上调。此外，还发现向盐抵抗性Sprague Dawley大鼠肾间质输注HO 3天，可独立于动脉血压升高而刺激mTORC1活性。这些数据共同表明，SS大鼠中盐诱导的肾脏HO增加激活了mTORC1通路。每天腹腔注射雷帕霉素（1.5毫克/千克/天），持续21天，可使SS大鼠盐诱导的高血压从176.0±9.0毫米汞柱降至153.0±12.0毫米汞柱，但对Sprague Dawley处理大鼠的血压盐敏感性没有影响。与赋形剂相比，雷帕霉素使SS大鼠的白蛋白排泄率从190.0±35.0毫克/天降至37.0±5.0毫克/天，并减少了皮质和髓质中T淋巴细胞（CD3）和巨噬细胞（ED1）的肾浸润。雷帕霉素处理的SS大鼠的肾肥大和细胞增殖也有所减少。我们得出结论，4.0%氯化钠饮食增强肾内HO可刺激mTORC1通路，这是SS大鼠盐诱导的高血压和肾损伤充分发展所必需的。
