Abstract: SA-PO283
Myokine SIRPα Leads to Defective Heart-Kidney Fatty Acid Oxidation in Type 1 Diabetes
Session Information
- Diabetic Kidney Disease: Basic - 2
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Zhang, Helena, Baylor College of Medicine, Houston, Texas, United States
- Wu, Jiao, Baylor College of Medicine, Houston, Texas, United States
- Thomas, Sandhya S., Baylor College of Medicine, Houston, Texas, United States
Background
Dysregulated insulin signaling has been associated with maladaptive alterations in metabolism, cardiac dysfunction and adverse remodeling contributing to cardio-renal diseases. We have previous identified myokine signal regulatory protein alpha (SIRPα), an endogenous mediator of insulin resistance, is upregulated in response to hyperglycemia or uremia, modulating heart-kidney crosstalk. The impact of cardiac-specific SIRPα knockout (KO) regulation on heart-kidney metabolism in the absence of insulin is largely unknown.
Methods
A single dose of 150 mg/kg of STZ was administered to (Myh6Cre)-control and cardiac-specific (cs) SIRPα KO mice. At five weeks post-treatment, M-mode transthoracic echocardiography was performed by an experienced sonographer who was blinded to the study groups. Real-time PCR analysis was used to quantify relative mRNA transcript levels of fetal genes in the heart, fatty acid oxidation genes, fibrotic genes, and inflammatory cytokines. Statistical significance was calculated using 2-tailed unpaired Student’s t test.
Results
Cardiac-specific SIRPα KO mice exposed to STZ exhibited improved cardiac output (ml/min), fractional shortening (%), and ejection fraction (%) compared to Myh6Cre-control mice with similar heart rates. STZ-treated csSIRPα KO mice displayed downregulation of fetal genes including ANP, BNP, and MHC-alpha as well as suppressed cardiac fibrosis when compared to control mice. These cardiac changes were importantly associated with a downregulation of transcripts encoding genes involved in fatty acid oxidation genes in both the heart and kidneys. Finally, kidney tissue from STZ-treated csSIRPα KO mice exhibited substantially decreased inflammatory markers and fibronectin when compared to control mice.
Conclusion
These results emphasize the role of myokine SIRPα in reprogramming of the fetal genes and cardiac dysfunction while contributing to kidney inflammation and fibrosis. Since chronic kidney disease is a significant independent risk factor for cardiovascular mortality, further examination is imperative in understanding the impact of dysregulated muscle metabolism, specifically myokine triggers on heart-kidney FAO responses independent of insulin in a model of type 1 diabetes.
Funding
- Veterans Affairs Support