Rapamycin attenuates atrial fibrosis in 5/6 nephrectomized rats by inhibiting mammalian target of rapamycin and profibrotic signaling

Background: Atrial fibrosis plays a vital role in the pathogenesis of atrial fibrillation. However, the complex interplay between inflammation and remodeling remains incompletely understood. In this study, we examined the potential beneficial effects of the immunosuppressant rapamycin on reverse atrial remodeling in a 5/6 nephrectomized (5/6Nx) rat model of chronic kidney disease (CKD). Materials and Methods: Sprague-Dawley male rats were housed under controlled conditions with constant temperature and humidity for 1 week before the operation. They were assigned randomly to the following groups: (1) sham procedure with vehicle treatment, (2) 5/6Nx group with vehicle treatment, and (3) 5/6Nx with rapamycin treatment. The 5/6Nx group underwent nephrectomy by resection of the upper and lower thirds of the left kidney, followed by right nephrectomy. The rapamycin group received daily rapamycin (1 mg/kg/day) from the 4th week to the 8th after operation. Results: A significant increase in the protein expression levels of mammalian target of rapamycin (mTOR), p38, and extracellular signal-regulated kinase was observed in the 5/6Nx + vehicle group (1.56 ± 0.12 vs. 0.72 ± 0.06; 2.64 ± 0.40 vs. 1.20 ± 0.20; and 3.02 ± 0.71 vs. 1.42 ± 0.34; all P < 0.05), which were suppressed by rapamycin treatment (0.88 ± 0.08 vs. 1.56 ± 0.12; 1.96 ± 0.21 vs. 2.64 ± 0.40; and 1.87 ± 1.87 vs. 3.02 ± 0.71; all P < 0.05). Cardiomyocyte hypertrophy and extensive interstitial fibrosis of the atrium were observed in the 5/6Nx + VEH group (P < 0.05). These changes were attenuated in the 5/6Nx + rapamycin group (P < 0.05). Conclusions: In this 5/6Nx CKD rat model, atrial fibrosis was mediated via the mTOR pathway, which was attenuated by rapamycin.