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    Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro-Fibrotic Signaling

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    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/Kā€ATPase. 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/Kā€ATPase 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 JEGā€3 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 JEGā€2 cells. Male Spragueā€Dawley 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 MBGā€mediated profibrotic signaling and provide support for beneficial effect of a novel therapy for uremic cardiomyopathy
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