SIRP alpha Mediates IGF1 Receptor in Cardiomyopathy Induced by Chronic Kidney Disease

Background: Chronic kidney disease (CKD) is characterized by increased myocardial mass despite near-normal blood pressure, suggesting the presence of a separate trigger. A potential driver is SIRP alpha (signal regulatory protein alpha)-a mediator impairing insulin signaling. The objective of this study is to assess the role of circulating SIRP alpha in CKD-induced adverse cardiac remodeling. Methods: SIRP alpha expression was evaluated in mouse models and patients with CKD. Specifically, mutant, muscle-specific, or cardiac muscle-specific SIRP alpha KO (knockout) mice were examined after subtotal nephrectomy. Cardiac function was assessed by echocardiography. Metabolic responses were confirmed in cultured muscle cells or cardiomyocytes. Results: We demonstrate that SIRP alpha regulates myocardial insulin/IGF1R (insulin growth factor-1 receptor) signaling in CKD. First, in the serum of both mice and patients, SIRP alpha was robustly secreted in response to CKD. Second, cardiac muscle upregulation of SIRP alpha was associated with impaired insulin/IGF1R signaling, myocardial dysfunction, and fibrosis. However, both global and cardiac muscle-specific SIRP alpha KO mice displayed improved cardiac function when compared with control mice with CKD. Third, both muscle-specific or cardiac muscle-specific SIRP alpha KO mice did not significantly activate fetal genes and maintained insulin/IGF1R signaling with suppressed fibrosis despite the presence of CKD. Importantly, SIRP alpha directly interacted with IGF1R. Next, rSIRP alpha (recombinant SIRP alpha) protein was introduced into muscle-specific SIRP alpha KO mice reestablishing the insulin/IGF1R signaling activity. Additionally, overexpression of SIRP alpha in myoblasts and cardiomyocytes impaired pAKT (phosphorylation of AKT) and insulin/IGF1R signaling. Furthermore, myotubes and cardiomyocytes, but not adipocytes treated with high glucose or cardiomyocytes treated with uremic toxins, stimulated secretion of SIRP alpha in culture media, suggesting these cells are the origin of circulating SIRP alpha in CKD. Both intracellular and extracellular SIRP alpha exert biologically synergistic effects impairing intracellular myocardial insulin/IGF1R signaling. Conclusions: Myokine SIRP alpha expression impairs insulin/IGF1R functions in cardiac muscle, affecting cardiometabolic signaling pathways. Circulating SIRP alpha constitutes an important readout of insulin resistance in CKD-induced cardiomyopathy.