{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T16:56:55Z","timestamp":1787936215858,"version":"build-2784847793"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2022,7,22]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>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\u03b1 (signal regulatory protein alpha)\u2014a mediator impairing insulin signaling. The objective of this study is to assess the role of circulating SIRP\u03b1 in CKD-induced adverse cardiac remodeling.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>SIRP\u03b1 expression was evaluated in mouse models and patients with CKD. Specifically, mutant, muscle-specific, or cardiac muscle\u2013specific SIRP\u03b1 KO (knockout) mice were examined after subtotal nephrectomy. Cardiac function was assessed by echocardiography. Metabolic responses were confirmed in cultured muscle cells or cardiomyocytes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>We demonstrate that SIRP\u03b1 regulates myocardial insulin\/IGF1R (insulin growth factor-1 receptor) signaling in CKD. First, in the serum of both mice and patients, SIRP\u03b1 was robustly secreted in response to CKD. Second, cardiac muscle upregulation of SIRP\u03b1 was associated with impaired insulin\/IGF1R signaling, myocardial dysfunction, and fibrosis. However, both global and cardiac muscle\u2013specific SIRP\u03b1 KO mice displayed improved cardiac function when compared with control mice with CKD. Third, both muscle-specific or cardiac muscle\u2013specific SIRP\u03b1 KO mice did not significantly activate fetal genes and maintained insulin\/IGF1R signaling with suppressed fibrosis despite the presence of CKD. Importantly, SIRP\u03b1 directly interacted with IGF1R. Next, rSIRP\u03b1 (recombinant SIRP\u03b1) protein was introduced into muscle-specific SIRP\u03b1 KO mice reestablishing the insulin\/IGF1R signaling activity. Additionally, overexpression of SIRP\u03b1 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\u03b1 in culture media, suggesting these cells are the origin of circulating SIRP\u03b1 in CKD. Both intracellular and extracellular SIRP\u03b1 exert biologically synergistic effects impairing intracellular myocardial insulin\/IGF1R signaling.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Myokine SIRP\u03b1 expression impairs insulin\/IGF1R functions in cardiac muscle, affecting cardiometabolic signaling pathways. Circulating SIRP\u03b1 constitutes an important readout of insulin resistance in CKD-induced cardiomyopathy.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.121.320546","type":"journal-article","created":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T09:00:38Z","timestamp":1655715638000},"page":"207-221","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["SIRP\u03b1 Mediates IGF1 Receptor in Cardiomyopathy Induced by Chronic Kidney Disease"],"prefix":"10.1161","volume":"131","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4993-8812","authenticated-orcid":true,"given":"Sandhya S.","family":"Thomas","sequence":"first","affiliation":[{"name":"Nephrology Division, Department of Medicine, Michael E. Debakey VA Medical Center, Houston, TX (S.S.T.)."},{"name":"Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, TX (S.S.T., J.W., M.W.H., Z.H., W.E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiao","family":"Wu","sequence":"additional","affiliation":[{"name":"Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, TX (S.S.T., J.W., M.W.H., Z.H., W.E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2771-6466","authenticated-orcid":true,"given":"Giovanni","family":"Davogustto","sequence":"additional","affiliation":[{"name":"Cardiology Division, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (G.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Holliday","sequence":"additional","affiliation":[{"name":"Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, TX (S.S.T., J.W., M.W.H., Z.H., W.E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Eckel-Mahan","sequence":"additional","affiliation":[{"name":"Center for Metabolic and Degenerative Diseases, Institute of Molecular Medicine, The University of Texas Health Science Center, Houston (K.E.-M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Verzola","sequence":"additional","affiliation":[{"name":"Nephrology Division, Department of Medicine, Universit\u00e0 degli Studi di Genova, Genoa, Italy (D.V., G.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6432-2429","authenticated-orcid":true,"given":"Giacomo","family":"Garibotto","sequence":"additional","affiliation":[{"name":"Nephrology Division, Department of Medicine, Universit\u00e0 degli Studi di Genova, Genoa, Italy (D.V., G.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoyong","family":"Hu","sequence":"additional","affiliation":[{"name":"Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, TX (S.S.T., J.W., M.W.H., Z.H., W.E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William E.","family":"Mitch","sequence":"additional","affiliation":[{"name":"Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, TX (S.S.T., J.W., M.W.H., Z.H., W.E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5434-6360","authenticated-orcid":true,"given":"Heinrich","family":"Taegtmeyer","sequence":"additional","affiliation":[{"name":"Cardiology Division, Department of Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston 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