Shimada Satoshi, Yang Chun, Kumar Vikash, Mattson David L, Cowley Allen W
Department of Physiology, Medical College of Wisconsin, Milwaukee (S.S., C.Y., V.K., D.L.M., A.W.C.).
Now with: Department of Physiology, Medical College of Georgia at Augusta University (D.L.M.).
Hypertension. 2022 Jun;79(6):1180-1189. doi: 10.1161/HYPERTENSIONAHA.121.18643. Epub 2022 Mar 16.
The present study in Sprague-Dawley rats determined the effects of a rapid rise of renal perfusion pressure (RPP) upon the activation of mTOR (mechanistic target of rapamycin), and the effects upon the infiltration of CD68-positive macrophages/monocytes and CD3-positive T lymphocytes into the kidneys.
RPP was elevated by 40 mm Hg for 30 minutes in male Sprague-Dawley rats while measuring renal blood flow and urine flow rate. Sham rats were studied in the same way, but RPP was not changed. Since initial studies found that the acute increase of RPP resulted in activation of mTORC1 (phosphorylation of S6), the effects of inhibition of mTORC1 with rapamycin pretreatment were then determined.
It was found that a 30-minute increase of RPP (≈40 mm Hg) resulted in an 8-fold increase of renal sodium excretion which was blunted by rapamycin treatment. Renal blood flow was not affected by the elevation of RPP. Activation of mTORC1 was observed. Significant increases in CD68-positive macrophages were found in both the cortex (intraglomerular and periglomerular regions) and in the outer medullary interstitial regions of the kidney and prevented by rapamycin treatment. Increases in CD3-positive T lymphocytes were observed exclusively in the periglomerular regions and prevented by rapamycin treatment. Upregulation of several proinflammatory markers was observed.
We conclude that elevation of RPP rapidly activates mTORC1 resulting in infiltration of immune cells into the kidney.
本研究在Sprague-Dawley大鼠中确定了肾灌注压（RPP）快速升高对雷帕霉素作用靶点（mTOR）激活的影响，以及对CD68阳性巨噬细胞/单核细胞和CD3阳性T淋巴细胞浸润肾脏的影响。
在测量肾血流量和尿流率的同时，将雄性Sprague-Dawley大鼠的RPP升高40 mmHg并持续30分钟。对假手术大鼠进行同样的研究，但RPP不改变。由于初步研究发现RPP的急性升高导致mTORC1激活（S6磷酸化），随后确定了雷帕霉素预处理对mTORC1的抑制作用。
发现RPP升高30分钟（约40 mmHg）导致肾钠排泄增加8倍，而雷帕霉素治疗可减弱这种增加。RPP升高未影响肾血流量。观察到mTORC1激活。在肾脏皮质（肾小球内和肾小球周围区域）和外髓质间质区域均发现CD68阳性巨噬细胞显著增加，雷帕霉素治疗可预防这种增加。仅在肾小球周围区域观察到CD3阳性T淋巴细胞增加，雷帕霉素治疗可预防这种增加。观察到几种促炎标志物上调。
我们得出结论，RPP升高可迅速激活mTORC1，导致免疫细胞浸润到肾脏。
