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Ghrelin Treatment of Chronic Kidney Disease: Improvements in Lean Body Mass and Cytokine Profile

Department of Pediatrics (M.D.D.), University of Virginia, Charlottesville, Virginia 22908; Center for the Study of Weight Regulation and Department of Pediatrics (X.Z., P.R.L., D.L.M.), Oregon Health and Science University, Portland, Oregon 97239; Department of Behavioral Medicine (A.I.), Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, 890-8520 Japan; Nephrology Division (Z.H., G.H., W.E.M.,), Department of Medicine, Baylor College of Medicine, Houston, Texas 77030; and IPSEN (J.E.T., H.A.H., J.Z.D., R.D., M.D.C.), Milford, Massachusetts 01757

Address all correspondence and requests for reprints to: Daniel L. Marks, 707 Southwest Gaines Road, CDRC-P, Portland, Oregon 97239. E-mail: marksd{at}ohsu.edu.

Chronic kidney disease (CKD) is associated with an increase in inflammatory cytokines and can result in cachexia with loss of muscle and fat stores. We previously demonstrated the efficacy of treating a model of cancer cachexia with ghrelin and a ghrelin receptor agonist. Currently, we examine a surgical model of CKD in rats, resulting in uremia and decreased accrual of lean body mass. Treatment with ghrelin and two ghrelin receptor agonists (BIM-28125 and BIM-28131) resulted in increased food intake and an improvement in lean body mass accrual that was related in part to a decrease in muscle protein degradation as assessed by muscle levels of the 14-kDa actin fragment resulting from cleaved actomyosin. Additionally, there was a decrease in circulating inflammatory cytokines in nephrectomized animals treated with ghrelin relative to saline treatment. Ghrelin-treated animals also had a decrease in the expression of IL-1 receptor in the brainstem and a decrease in expression of prohormone convertase-2, an enzyme involved in the processing of proopiomelanocortin to the anorexigenic peptide -MSH. We conclude that ghrelin treatment in uremia results in improved lean mass accrual in part due to suppressed muscle proteolysis and possibly related to antiinflammatory effects.

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