IL-6 and Serum Amyloid A Synergy Mediates Angiotensin II–Induced Muscle Wasting
Open Access
- 1 March 2009
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 20 (3), 604-612
- https://doi.org/10.1681/asn.2008060628
Abstract
Animal studies suggest that increased levels of circulating angiotensin II (AngII) could contribute to the loss of lean body mass in chronic kidney disease, but the mechanism by which this occurs is unclear. Here, AngII infusion increased circulating IL-6 and its hepatic production in wild-type mice, suggesting that AngII-induced inflammation may trigger muscle loss. AngII infusion also stimulated the suppressor of cytokine signaling (SOCS3) in muscle, which led to loss of insulin receptor substrate 1 (IRS-1), thereby impairing insulin/IGF-1 signaling and enhancing protein degradation. All of these responses to AngII were suppressed in IL-6–deficient mice. Recombinant human IL-6 (rhIL-6) treatment of cultured myotubes only minimally increased SOCS3, however, suggesting the contribution of other mediators. Because AngII increases hepatic serum amyloid A (SAA) expression in an IL-6–dependent manner, we treated wild-type mice with rhIL-6 and an SAA1-overexpressing adenovirus; the combination led to a significantly greater increase in SOCS3 and decrease in IRS-1 compared with either rhIL-6 or SAA1 alone. We observed similar effects on SOCS3 and IRS-1 when we treated cultured muscle myotubes with rhIL-6 and SAA1. Taken together, these results suggest an interorgan response to high levels of AngII: Hepatic production of IL-6 and SAA increases, and these mediators act synergistically to impair insulin/IGF-1 signaling, which promotes muscle proteolysis. Targeting the high levels of IL-6 and SAA in catabolic disorders might be a therapeutic approach to prevent muscle wasting.Keywords
This publication has 44 references indexed in Scilit:
- A proposed nomenclature and diagnostic criteria for protein–energy wasting in acute and chronic kidney diseaseKidney International, 2008
- Adenosine A2Areceptor activation and macrophage‐mediated experimental glomerulonephritisThe FASEB Journal, 2007
- Human Serum Amyloid A Protein Inhibits Hepatitis C Virus Entry into CellsJournal of Virology, 2007
- Variation in ACE activity affects myogenic differentiation in C2C12 cellsBiochemical and Biophysical Research Communications, 2007
- Development of a Diagnostic Method for Detecting Increased Muscle Protein Degradation in Patients with Catabolic ConditionsJournal of the American Society of Nephrology, 2006
- IL-6 signaling via the STAT3/SOCS3 pathway: Functional Analysis of the Conserved STAT3 N-domainMolecular and Cellular Biochemistry, 2006
- Dual Pathways for Nuclear Factor κB Activation by Angiotensin II in Vascular Smooth MuscleCirculation Research, 2005
- IL-10, IL-6, and TNF-α: Central factors in the altered cytokine network of uremia—The good, the bad, and the uglyKidney International, 2005
- The IGF-1/PI3K/Akt Pathway Prevents Expression of Muscle Atrophy-Induced Ubiquitin Ligases by Inhibiting FOXO Transcription FactorsMolecular Cell, 2004
- Wasting as independent risk factor for mortality in chronic heart failureThe Lancet, 1997