Uremic cardiac hypertrophy is reversed by rapamycin but not by lowering of blood pressure.
Chronic kidney disease is often complicated by uremic cardiomyopathy that consists of left ventricular hypertrophy and interstitial fibrosis. It is thought that hypertension and volume overload are major causes of this disease, but here we sought to identify additional mechanisms using a mouse model of chronic renal insufficiency. Mice with a remnant kidney developed an elevated blood urea nitrogen by 1 week, as expected, and showed progressive cardiac hypertrophy and fibrosis at 4 and 8 weeks even though their blood pressures were not elevated nor did they show signs of volume overload. Cardiac extracellular signal-regulated kinase (ERK) was activated in the uremic animals at 8 weeks. There was also an increased phosphorylation of S6 kinase, which is often mediated by activation of the mammalian target of rapamycin (mTOR). To test the involvement of this pathway, we treated these uremic mice with rapamycin and found that it reduced cardiac hypertrophy. Reduction of blood pressure, however, by hydralazine had no effect. These studies suggest that uremic cardiomyopathy is mediated by activation of a pathway that involves the mTOR pathway.
Siedlecki
Andrew M
AM
The Center for Cardiovascular Research, John Milliken Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Jin
Xiaohua
X
Muslin
Anthony J
AJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy*; D002312:Cardiomyopathy, Hypertrophic / Q000209:etiology*; D002352:Carrier Proteins / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006830:Hydralazine / Q000494:pharmacology; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
D002352:Carrier Proteins; D006830:Hydralazine; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020123:Sirolimus