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We established that replacement of lost substance P (SP) that occurs in T2DM reduces cardiac fibrosis and decreases inflammation in T2DM mice and non\u2010human primates. This study aimed to identify the specific anti\u2010fibrotic SP receptor.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      Age\u2010matched male wild type (WT) and Lepr\n                      <jats:sup>db\/db<\/jats:sup>\n                      mice at 12\u2009weeks of age were treated with either saline or the neurokinin\u20101 receptor (NK\u20101R) agonist, GR73632 (300\u2009\u03bcg\u00b7kg\n                      <jats:sup>\u22121<\/jats:sup>\n                      \u00b7day\n                      <jats:sup>\u22121<\/jats:sup>\n                      ) for 4\u2009weeks. The left ventricles were assessed for cardiac function, fibrosis, mast cells and macrophage phenotype. Mouse cardiac fibroblast and bone marrow\u2010derived macrophage cultures were exposed to high glucose and treated with GR73632 to assess collagen release, signalling pathways and cytokine release respectively. Proteomics analysis was conducted to assess the left ventricular proteomic profile between WT and Lepr\n                      <jats:sup>db\/db<\/jats:sup>\n                      mice, and the effects of GR73632.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      NK\u20101R activation decreased cardiac fibrosis, improved diastolic function, decreased mast cell numbers and promoted an anti\u2010inflammatory macrophage phenotype in Lepr\n                      <jats:sup>db\/db<\/jats:sup>\n                      mice. NK\u20101R activation reduced collagen I production by high glucose treated mouse cardiac fibroblasts. NK\u20101R activation decreased P65 phosphorylation (NF\u2010\n                      <jats:italic>\u03ba<\/jats:italic>\n                      B) and CCL2 chemokine release. Proteomic analysis revealed a distinct proteome profile between WT and Lepr\n                      <jats:sup>db\/db<\/jats:sup>\n                      mouse hearts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>The NK\u20101R is the anti\u2010fibrotic SP receptor and improves diastolic function in the diabetic heart. This likely involves direct effects on cardiac fibroblasts and macrophages. This study provides a potential target for treatment of diabetic cardiomyopathy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70440","type":"journal-article","created":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T08:45:43Z","timestamp":1777106743000},"page":"4246-4266","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neurokinin\u20101 receptor activation protects against cardiac fibrosis, inflammation and diastolic dysfunction in type 2 diabetic mice"],"prefix":"10.1111","volume":"183","author":[{"given":"Alexander","family":"Widiapradja","sequence":"first","affiliation":[{"name":"Robert C. Byrd Health Sciences Center, Department of Physiology, Pharmacology and Toxicology West Virginia University  Morgantown West Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Connery","sequence":"additional","affiliation":[{"name":"Robert C. Byrd Health Sciences Center, Department of Physiology, Pharmacology and Toxicology West Virginia University  Morgantown West Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brody J.","family":"Helmick","sequence":"additional","affiliation":[{"name":"Robert C. Byrd Health Sciences Center, Department of Physiology, Pharmacology and Toxicology West Virginia University  Morgantown West Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kallie J.","family":"Schafner","sequence":"additional","affiliation":[{"name":"Robert C. Byrd Health Sciences Center, Department of Physiology, Pharmacology and Toxicology West Virginia University  Morgantown West Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vamsi","family":"Manchikalapudi","sequence":"additional","affiliation":[{"name":"Robert C. 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