A Pegylated Leptin Antagonist Ameliorates CKD-Associated... : Journal of the American Society of Nephrology (original) (raw)

Basic Research

Cheung, Wai W.*; Ding, Wei†; Gunta, Sujana S.*; Gu, Yong†; Tabakman, Rinat‡; Klapper, Leah N.‡; Gertler, Arieh§; Mak, Robert H.*

*Division of Pediatric Nephrology, University of California, San Diego, La Jolla, California;

†Division of Nephrology, The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai, China;

‡BioLine Innovations, Jerusalem, Israel; and

§Institute of Biochemistry, Food Science and Nutrition, Hebrew University of Jerusalem, Rehovot, Israel

Correspondence: Prof. Robert H. Mak, Pediatric Nephrology, University of California, San Diego, 9500 Gilman Drive, MC0634, La Jolla, CA 92093-0634. Email: [email protected]

Received April 29, 2013

Accepted July 5, 2013

Abstract

Elevated serum leptin levels correlate with inflammation and predict changes in lean body mass in patients with CKD, and activation of the melanocortin system by leptin signaling mediates the pathophysiology of CKD-associated cachexia. We tested whether treatment with a pegylated leptin receptor antagonist (PLA) attenuates cachexia in mice with CKD. CKD and Sham mice received vehicle or PLA (2 or 7 mg/kg per day). At these doses, PLA did not influence serum leptin levels in mice. Treatment with 7 mg/kg per day PLA stimulated appetite and weight gain, improved lean mass and muscle function, reduced energy expenditure, and normalized the levels of hepatic TNF-α and IL-6 mRNA in mice with CKD. Furthermore, treatment with 7 mg/kg per day PLA attenuated the CKD-associated increase in the transcriptional and protein abundance of uncoupling proteins that mediates thermogenesis, and it normalized the molecular signatures of processes associated with muscle wasting in CKD, including proteolysis, myogenesis and muscle regeneration, and expression of proinflammatory muscle cytokines, such as IL-1α, -1β, and -6 and TNF-α. Our results suggest that leptin antagonism may represent a viable therapeutic strategy for cachexia in CKD.