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 SIRPα (signal regulatory protein alpha)—a mediator impairing insulin signaling. The objective of this study is to assess the role of circulating SIRPα in CKD-induced adverse cardiac remodeling.Methods:SIRPα expression was evaluated in mouse models and patients with CKD. Specifically, mutant, muscle-specific, or cardiac muscle–specific SIRPα 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 SIRPα regulates myocardial insulin/IGF1R (insulin growth factor-1 receptor) signaling in CKD. First, in the serum of both mice and patients, SIRPα was robustly secreted in response to CKD. Second, cardiac muscle upregulation of SIRPα was associated with impaired insulin/IGF1R signaling, myocardial dysfunction, and fibrosis. However, both global and cardiac muscle–specific SIRPα KO mice displayed improved cardiac function when compared with control mice with CKD. Third, both muscle-specific or cardiac muscle–specific SIRPα KO mice did not significantly activate fetal genes and maintained insulin/IGF1R signaling with suppressed fibrosis despite the presence of CKD. Importantly, SIRPα directly interacted with IGF1R. Next, rSIRPα (recombinant SIRPα) protein was introduced into muscle-specific SIRPα KO mice reestablishing the insulin/IGF1R signaling activity. Additionally, overexpression of SIRPα 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 SIRPα in culture media, suggesting these cells are the origin of circulating SIRPα in CKD. Both intracellular and extracellular SIRPα exert biologically synergistic effects impairing intracellular myocardial insulin/IGF1R signaling.Conclusions:Myokine SIRPα expression impairs insulin/IGF1R functions in cardiac muscle, affecting cardiometabolic signaling pathways. Circulating SIRPα constitutes an important readout of insulin resistance in CKD-induced cardiomyopathy.

中文翻译：

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SIRPα 介导慢性肾病引起的心肌病中的 IGF1 受体

背景：慢性肾病（CKD）的特点是尽管血压接近正常，但心肌质量增加，这表明存在单独的触发因素。一个潜在的驱动因素是 SIRPα（信号调节蛋白 α）——一种损害胰岛素信号传导的介质。本研究的目的是评估循环SIRPα在CKD诱导的不良心脏重塑中的作用。方法：在小鼠模型和CKD患者中评估SIRPα的表达。具体来说，在肾次全切除术后对突变型、肌肉特异性或心肌特异性 SIRPα KO（基因敲除）小鼠进行检查。通过超声心动图评估心脏功能。代谢反应在培养的肌肉细胞或心肌细胞中得到证实。结果：我们证明 SIRPα 调节 CKD 中的心肌胰岛素/IGF1R（胰岛素生长因子 1 受体）信号传导。首先，在小鼠和患者的血清中，SIRPα 因 CKD 反应而大量分泌。其次，心肌中 SIRPα 的上调与胰岛素/IGF1R 信号传导受损、心肌功能障碍和纤维化有关。然而，与 CKD 对照小鼠相比，整体和心肌特异性 SIRPα KO 小鼠的心脏功能均有所改善。第三，尽管存在 CKD，但肌肉特异性或心肌特异性 SIRPα KO 小鼠均未显着激活胎儿基因，并维持胰岛素/IGF1R 信号传导并抑制纤维化。重要的是，SIRPα 直接与 IGF1R 相互作用。接下来，将 rSIRPα（重组 SIRPα）蛋白引入肌肉特异性 SIRPα KO 小鼠中，重建胰岛素/IGF1R 信号传导活性。此外，成肌细胞和心肌细胞中 SIRPα 的过度表达会损害 pAKT（AKT 磷酸化）和胰岛素/IGF1R 信号传导。此外，肌管和心肌细胞（但不是用高葡萄糖处理的脂肪细胞或用尿毒症毒素处理的心肌细胞）刺激培养基中 SIRPα 的分泌，表明这些细胞是 CKD 中循环 SIRPα 的起源。细胞内和细胞外SIRPα均发挥生物协同作用，损害细胞内心肌胰岛素/IGF1R信号传导。结论：Myokine SIRPα表达损害心肌中胰岛素/IGF1R功能，影响心脏代谢信号通路。循环 SIRPα 是 CKD 诱发的心肌病中胰岛素抵抗的重要指标。