1 research outputs found
Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro-Fibrotic Signaling
Background: Experimental uremic cardiomyopathy causes cardiac fibrosis and is causally related to the increased circulating levels of the cardiotonic steroid, marinobufagenin (MBG), which signals through Na/KāATPase. Rapamycin is an inhibitor of the serine/threonine kinase mammalian target of rapamycin (mTOR) implicated in the progression of many different forms of renal disease. Given that Na/KāATPase signaling is known to stimulate the mTOR system, we speculated that the ameliorative effects of rapamycin might influence this pathway.
Methods and Results: Biosynthesis of MBG by cultured human JEGā3 cells is initiated by CYP27A1, which is also a target for rapamycin. It was demonstrated that 1 Ī¼mol/L of rapamycin inhibited production of MBG in human JEGā2 cells. Male SpragueāDawley rats were subjected to either partial nephrectomy (PNx), infusion of MBG, and/or infusion of rapamycin through osmotic minipumps. PNx animals showed marked increase in plasma MBG levels (1025Ā±60 vs 377Ā±53 pmol/L; PPP
Conclusions: Rapamycin treatment in combination with MBG infusion significantly attenuated cardiac fibrosis. Our results suggest that rapamycin may have a dual effect on cardiac fibrosis through (1) mTOR inhibition and (2) inhibiting MBGāmediated profibrotic signaling and provide support for beneficial effect of a novel therapy for uremic cardiomyopathy