Studies were carried out to determine whether acute elevation of renal perfusion pressure (RPP) activates the mechanistic target of rapamycin complex 1 (mTORC1) and inflammation-related genes which may trigger a rapid infiltration of immune cells. RPP was elevated by 40 mmHg (HP group) for 30 minutes in male SD rats (n=5, 10-12 weeks of age) while measuring renal blood flow (RBF; Transonic ultrasonic probe) and urine flow rate. Sham rats (Sham group) 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 (pS6 S235/6 /S6; P<0.05) but not mTORC2 (pAKT T308 /AKT ), the effects of inhibition of mTORC1 with rapamycin (Rapa) pretreatment (1.5 mg/kg; n=10) were then determined (HP+Rapa group). RBF was well autoregulated in both HP and HP+Rapa treated rats averaging 6.9 ± 0.5 vs 7.0 ± 0.8 ml/min/gkw in HP (p=0.72) and 8.1 ± 0.8 vs 8.4 ± 0.5 in HP+Rapa group (p=0.34) with a 40 mmHg elevation of RPP. Pressure-natriuresis was unexpectedly blunted in HP+Rapa treated rats increasing from 0.40 ± 0.21 to 4.0 ± 1.1 in HP rats compared to 0.21 ± 0.07 to 2.3 ± 0.5 μmol/min/gkw; p<0.05) in the HP+Rapa treated rats. Urine volumes were similarly affected. Elevation of RPP increased the mTORC1 activity (pS6 S235/6 /S6) in renal cortex (2.8 ± 0.4 vs 4.8 ± 0.5 A.U.; p<0.05, n=5) and outer medulla (2.0 ± 0.3 vs 5.0 ± 0.6 A.U.; p<0.05, n=5) of HP rats compared to Sham. Rapa treatment suppressed this activation. rtPCR analysis found increased mRNA expression of lipocalin-2 (Lcn2; involved innate immune responses; p<0.05), heme oxygenase (Hmox1; p<0.05) and cyclooxygenase 2 (Cox2; p=0.08) in HP rats compared to Sham, responses which were generally blunted by Rapa. Importantly, as determined by immunohistochemistry, CD68 positive macrophage staining was significantly increased (p<0.001) with elevation of RPP in HP compared to sham rat kidneys. This was significantly reduced by Rapa treatment (p<0.001). We conclude that the mTORC1 pathway can be activated very quickly following elevations of RPP and appears to be responsible for rapid macrophage infiltration which is prevented by Rapa treatment. So too, inhibition of mTORC1 with Rapa reduced the pressure-diuresis response through yet unknown mechanisms.