Abstract: SA-PO785
Myokine SIRPα Causes Insulin Resistance Promoting Organ Cross-Talk in CKD
Session Information
- CKD: Mechanisms - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Saeed, Maryam K., Baylor College of Medicine, Houst, Texas, United States
- Wu, Jiao, Baylor College of Medicine, Houst, Texas, United States
- Mitch, William E., Baylor College of Medicine, Houst, Texas, United States
- Thomas, Sandhya S., Baylor College of Medicine, Houst, Texas, United States
Background
Signal regulatory protein alpha (SIRPα), a substrate for tyrosine phosphatases, promotes insulin resistance. SIRPα regulation in skeletal muscle and systemic responses to distant organs is largely unknown. Here we examine the influences of circulating SIRPα induced by chronic kidney disease (CKD) or hyperglycemia on disturbing insulin signaling pathways related to metabolism.
Methods
CKD was induced in muscle-specific and fat-specific SIRPα KO mice and compared to control mice and serum levels of SIRPα were evaluated. Next, acute hyperglycemia was induced in control and organ-specific SIRPα KO mice and serum levels of SIRPα were evaluated. Next, exogenous administration of recombinant SIRPα was utilized to treat control mice and skeletal muscle insulin signaling was determined. Finally, serum samples were obtained from CKD patients prior to peritoneal dialysis catheter placement and healthy control samples were obtained from blood donors.
Results
In control mice with CKD serum SIRPα levels were increased, while in muscle-specific SIRPα KO mice with CKD, we uncovered that serum SIRPα levels (p<0.05) were suppressed and associated with improved insulin signaling both in skeletal muscles and adipose tissue. However, in adipose-specific SIRPα KO mice with CKD, levels of serum SIRPα were increased over 2-fold (p<0.05) while muscle losses were minimally inhibited. Additionally, when acute hyperglycemia was induced in control mice and and organ-specific SIRPα KO mice, serum SIRPα levels were significantly increased in response to hyperglycemia in control and adipose-specific SIRPα KO, but not muscle-specific SIRPα KO mice. Next, recombinant SIRPα was injected into mice and skeletal muscle insulin signaling was significantly impaired by exogenous administration. Finally, SIRPα signaling is clinically relevant as suggested by our findings that include increased serum SIRPα expression in the serum of patients with CKD (2.4-fold, p=0.000017 vs. Healthy Controls).
Conclusion
SIRPα plays an important role as an anti-insulin myokine regulating insulin-mediated pathways. In muscle-specific KO mice with CKD, changes in serum SIRPα levels improve insulin signaling in muscle and adipose tissue, suggesting organ crosstalk. Therefore, targeting SIRPα may prevent metabolic dysregulation and insulin resistance in patients with CKD.
Funding
- Veterans Affairs Support