| Popis: |
Cardiotonic steroids such as marinobufagenin (MBG) and ouabain are specific ligands for the Na/K-ATPase and represent a relatively new class of steroid hormones. Uremic cardiomyopathy is characterized by a decrease in diastolic function, left ventricular hypertrophy, oxidant stress, and both cardiac and renal fibrosis. We have shown that MBG, signaling through the Na/K-ATPase, causes many of the adverse pathological effects of experimental uremic cardiomyopathy induced by 5/6th nephrectomy (PNx) in the rat. The goal of this dissertation is to describe some of the manipulations we have performed in order to provide potential therapies for the treatment of uremic cariomyopathy. Specifically, we show that treatment with an anti-MBG antibody drastically reduces cardiac fibrosis in PNx animals. Treatment with rapamycin (an mTOR inhibitor) produced similar effects with the added benefit of reducing circulating MBG in these animals. In addition, we show that ischemic renal disease is accompanied with elevated levels of the platelet activation marker soluble CD40 ligand (sCD40L), and its soluble receptor, CD40, may predict outcomes in this disease state. Data in our PNx model suggests a role for proximal tubular CD40 activation contributing to the development of renal fibrosis, which may be potentiated by cardiotonic steroid signaling through the Na/K-ATPase. |
