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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/K‐ ATP ase. 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‐ ATP ase 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  CYP 27A1, which is also a target for rapamycin. It was demonstrated that 1 μmol/L of rapamycin inhibited production of  MBG  in human  JEG ‐2 cells. Male Sprague‐Dawley rats were subjected to either partial nephrectomy ( PN x), infusion of  MBG , and/or infusion of rapamycin through osmotic minipumps.  PN x 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  PN x‐rapamycin animals compared to  PN x (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.

journal of the american heart association

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