Abstract: SA-PO901
Leptin Signaling Blockade Ameliorates Muscle Wasting, Bone Disease, and Growth Failure in CKD
Session Information
- Mineral Disease: CKD-Bone
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Mineral Disease
- 1203 Mineral Disease: CKD-Bone
Authors
- Cheung, Wai W., UCSD, La Jolla, California, United States
- Iwaniec, Urszula T, Oregon State University, Corvalis, Oregon, United States
- Hao, Sheng, UCSD, La Jolla, California, United States
- Wang, Zhen, UCSD, La Jolla, California, United States
- Turner, Russell T, Oregon State University, Corvalis, Oregon, United States
- Mak, Robert H., UCSD, La Jolla, California, United States
Background
We showed that aberrant leptin signaling is important in the pathophysiology of CKD-associated wasting (Cheung W et al JCI 115:1659-65, 2005 & JASN 25:119-28, 2014). As muscle and bone health are related, we investigated whether leptin signaling blockade affects bone disease and growth failure in CKD.
Methods
We performed 5/6 nephrectomy (CKD) or sham-operation (S) in 8 week old c57BL/6J wild-type (WT), leptin-deficient (ob/ob) and leptin receptor deficient (db/db) mice. Then, WT-CKD mice were treated with a pegylated leptin antagonist (PLA) (7 mg/kg/day) or vehicle (V) for 4 weeks. Secondary hyperparathyroidism was restricted with low phosphorus diets. WT-CKD mice were fed ad libitum while all other mice were pair-fed to that of WT-CKD. Body composition was determined by EchoMRI. Whole body and femoral mineral content (BMC) and bone mineral density (BMD) were assessed by dual-energy x-ray absorptiometry. Femoral bone strength and bone architecture were assessed by 3-point failure load test and X-ray microtomographic scanning (μCT), respectively.
Results
WT-CKD, ob/ob-CKD, db/db-CKD, WT-CKD+PLA and WT-CKD+V mice had significantly higher blood urea nitrogen and serum creatinine than WT-S, ob/ob-S, db/db-S, WT-S+PLA and WT-S+V mice. Bone disease in WT-CKD mice was characterized by decreased whole body BMC, BMD as well as decreased femoral length, BMC, BMD, cortical area, thickness and failure load. μCT confirmed that femoral bone volume, cortical area and thickness were significantly reduced in WT-CKD. Uremic bone phenotype was significantly improved in ob/ob-CKD and db/db-CKD compared to WTCKD mice. Weight gain, lean mass and muscle function were normalized in WTCKD+PLA relative to WT-S+V mice. Increased expressions of muscle inflammatory cytokines (IL-1α, IL-1β, IL-6 and TNF-α) were normalized in WT-CKD+PLA relative to WT-S+V mice. Uremic bone disease was prevented in WT-CKD+PLA mice. Whole body BMC, BMD as well as femoral length BMD, BMC, and failure load were normalized in WT-CKD+PLA relative to WT-S+V mice.
Conclusion
Aberrant leptin signaling may play an important role in the pathogenesis of muscle wasting, osteodystrophy and growth failure in CKD. Its blockade may represent a novel therapeutic strategy.
Funding
- Clinical Revenue Support