SIRPα Contributions to Muscle Kidney Cross-Talk in Diabetic Kidney Disease
- Diabetic Kidney Disease: Basic - II
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
- Wu, Jiao, Baylor College of Medicine, Houston, Texas, United States
- Hu, Zhaoyong, Baylor College of Medicine, Houston, Texas, United States
- Thomas, Sandhya S., Baylor College of Medicine, Houston, Texas, United States
Fatty acid oxidation (FAO) is a preferred energy source for highly metabolic cells including cardiomyocytes and proximal tubular cells. The kidney is second only to the heart in mitochondrial numbers and oxygen consumption. ATP generation occurs mainly through fatty acid oxidation in the proximal tubular cells. Lipotoxicity has been linked to worsening kidney disease. Specifically, ATP depletion increases lipid accumulation, tubular necrosis and maladaptive repair ultimately leading to kidney dysfunction. Here we examined the role of muscle mediator, signal regulatory protein alpha (SIRPα) and its role in kidney FAO and function. Circulating serum SIRPα has been identified in patients with CKD, therefore we have examined the effects of SIRPα in a diabetic model of kidney disease.
Control flox mice, muscle (m)-specific and adipose (ad)-specific SIRPα knockout (KO) mice were subjected to a 60% high fat diet and compared to mice on standard chow. Metabolic processes including mRNA, protein expression, and oxygen consumption rates (Seahorse Bioscience) were identified. Triglyceride content was evaluated by triglyceride clearance assay.
Control flox mice display elevated levels of serum SIRPα in response to HFD. mSIRPα KO mice but not adipose-specific SIRPα KO mice exhibit evidence of improved body weight, intracellular insulin signaling in peripheral tissues, and adipokine profile. Additionally, these mice demonstrate less intramuscular fat when compared to control mice on HFD. Also, exogenous SIRPα impaired proximal tubular FAO while reducing ATP production. Finally, kidney tissues in mSIRPα KO mice unlike adSIRPα KO mice displayed improved renal fatty acid oxidation, a reduction in kidney triglyceride content, less kidney fibrosis, and importantly protection against diabetic kidney disease (cystatin C similar to control) despite obesity-induced diet.
These results suggest the importance of the muscles contribution to kidney disease, specifically, myokine SIRPα in exacerbating diabetic kidney disease. Our discoveries provide insight in correcting metabolic defects associated with kidney FAO and to prevent diabetic kidney disease.
- Private Foundation Support