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/k-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/k-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 jeg-3 cells is initiated by cyp27a1,which is also a target for rapamycin. it was demonstrated that 1 lmol/l of rapamycin inhibited production of mbg in human jeg-2 cells. male sprague- 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 (1025±60 vs 377±53 pmol/l; p<0.01),systolic blood pressure (169±1 vs 111±1 mm hg; p<0.01),and cardiac fibrosis compared to controls. plasma mbg levels were significantly decreased in pnx-rapamycin animals compared to pnx (373±46 vs 1025±60 pmol/l; p<0.01),and cardiac fibrosis was substantially attenuated by rapamycin treatment. 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 mbg-mediated profibrotic signaling and provide support for beneficial effect of a novel therapy for uremic cardiomyopathy. © 2016 the authors.