Chronic Kidney Disease-Induced Defects Initiated by SIRPα

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Chronic kidney disease (CKD) is a major public health problem, afflicting an estimated 15% (37 million) of US adults. Among Veterans, the prevalence of CKD is nearly 50% higher than that of the US general population. CKD-associated mortality is significantly higher than that of the general population and worsens with each stage of progressive CKD. The reason for these adverse outcomes is generally attributed to the development of cardiovascular disease and changes in myocardial size. There are several critical gaps in our current knowledge of cardiac remodeling in CKD. Our long term goal is to identify the molecular mechanisms responsible for CKD-induced cardiomyopathy. We have previously identified that signal regulatory protein alpha (SIRPα) is upregulated as a mediator of CKD-induced insulin resistance in skeletal muscles. Specifically, that CKD stimulates inflammation to upregulate SIRPα in skeletal muscles of mice and patients with CKD. Subsequently, SIRPα promotes insulin resistance in skeletal muscles and adipose tissue causing cachexia. CKD stimulates the opposite responses in the heart with increases in myocardial mass. The significance of our proposal is that we provide evidence for a differential role of SIRPα in mediating cachexia in skeletal muscles and adipose tissues while contributing to the development of increased cardiac muscle growth. We predict cardiac remodeling in CKD may be the result of impairments in myocardial insulin/insulin growth factor-1 (IGF1) receptor signaling. CENTRAL HYPOTHESIS: SIRPα behaves as a novel myokine impairing myocardial insulin/IGF1 receptor functions while promoting CKD-induced cardiomyopathy. Guided by strong preliminary data we propose three Specific Aims to characterize the metabolic milieu of CKD and its effects on myocardial mass: (1) Determine if SIRPα exacerbates myocardial insulin/IGF1 receptor signaling in CKD. (2) Identify CKD-specific (i.e. uremia) triggers that cause SIRPα release. (3) Evaluate the anti-proteolytic effects of SIRPα in modulating myocardial protein turnover in CKD. Our goal is to determine if SIRPα interacts with insulin/IGF1 receptor impairing intracellular signaling to promote myocardial growth and cardiac dysfunction. This discovery will stimulate novel targets for therapies to prevent CKD-associated heart failure and potentially improve the lives of Veterans suffering from its deleterious consequences.