Chronic kidney disease (CKD) frequently causes muscle wasting but there are no regularly effective means of blocking this complication of CKD. This is unfortunately because loss of muscle mass is associated with increased morbidity and mortality in these patients as in patients with other types of catabolic conditions. Because there is no readily available therapy to block muscle wasting, I am interested in designing treatment strategies to prevent loss of muscle. To date, we have found that complications of CKD stimulate the breakdown of muscle proteins. Specific complications that stimulate muscle loss include: accumulation of acid in the body, resistance to the benefits of insulin and increased production of hormones that cause muscle wasting (i.e., glucocorticoids). We also find that an excess of angiotensin II stimulates loss of muscle mass as does the presence of inflammation. Our goal is to identify treatments that prevent loss of muscle. Specifically, we have identified that CKD stimulates an increase in the activation of Stat3 (i.e., p-Stat3) in muscles of patients with CKD;this also is present in mice with CKD model. These results are encouraging because they point to a potential therapy, namely, inhibition of the activation of Stat3. Our proposed experiments are to analyze the importance of a small molecule, C188-9, which can be administrated orally. In fact, when we used C188-9 to inhibit the activation of Stat3, muscle wasting was reversed in mice with CKD.
Our Specific Aims are to: 1) To determine the pharmacokinetics and pharmacodynamics of C188-9 in rats with CKD. We will determine the optimal dose, route and frequency of C188-9 administration for treatment of CKD-induced cachexia. C188-9 will be administered orally or IP to rats with CKD since we have already studied the responses of mice. We will identify the minimum oral dose and frequency of administration for maintaining stable plasma levels of C188-9 above the dose in rats with CKD that achieved suppression of muscle wasting (i.e., 3 M in cells). We also will examine the concentration of C188-9 in muscle to associate this level with blocking muscle wasting. 2). To determine the efficacy of C188-9 in suppressing muscle wasting in rats with CKD. Based on results of specific Aim 1, we will use the optimal route, dose and frequency of C188-9 to treat rats with CKD. Changes in muscle mass, elements of the signaling pathway, muscle function and survival rates will be evaluated. Thus, our goal is to identify if C188-9 will effectively bloc CKD-induced muscle wasting in rodents. This information is absolutely required to develop C188-9 ultimately into a treatment for patients with CKD.
Muscle wasting complicates Chronic Kidney Disease (CKD) producing generalized weakness and debilitation and even life-shortening. Unfortunately, there are no effective means of blocking CKD-induced muscle wasting but we found that an inhibitor of Stat3 activation improves muscle mass and strength. We will determine the pharmacokinetics and pharmacodynamics of C188-9 in rats with CKD to provide insights that will lead to the development of strategies that combat muscle CKD and wasting disorders.
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