{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,9]],"date-time":"2026-11-09T17:02:45Z","timestamp":1794243765920,"version":"4.9.0"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Hypertension"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:p>\n                    The progression of diabetic kidney disease (DKD), a leading cause of end-stage kidney disease, involves mineralocorticoid receptor (MR) activation. We previously identified crosstalk between the small guanosine triphosphatase (GTPase) RAS-related C3 botulinus toxin substrate 1 (Rac1) and MR, but the role of Rac1-MR pathway activation in the progression of DKD is not clear. We performed uninephrectomy on type 2 diabetic mouse models,\n                    <jats:italic>db\/db<\/jats:italic>\n                    (UNx-high salt [HS]\n                    <jats:italic>db\/db<\/jats:italic>\n                    ), and their lean control,\n                    <jats:italic>db\/m<\/jats:italic>\n                    (UNx-HS\n                    <jats:italic>db\/m<\/jats:italic>\n                    ), at 4-week postpartum, and fed them a high-salt diet for 10 weeks. To evaluate the involvement of the Rac1-MR pathway in the DKD progression, we investigated the effects of the nonsteroidal MR antagonist, finerenone, and the Rac1 inhibitor, NSC23766, on blood pressure and glomerular injury in UNx-HS\n                    <jats:italic>db\/db<\/jats:italic>\n                    mice. UNx-HS\n                    <jats:italic>db\/db<\/jats:italic>\n                    mice with hyperaldosteronism showed hypertension and hypokalemia with increased cleaved \u03b1-epithelial sodium channel expressions and massive albuminuria, accompanied by glomerular injury with nodular lesions, which is a characteristic finding in human diabetic nephropathy. Expressions of active Rac1 and serum-and glucocorticoid-induced protein kinase 1 (Sgk1), a downstream molecule of MR signaling, in the renal cortex and isolated glomeruli, significantly elevated in UNx-HS\n                    <jats:italic>db\/db<\/jats:italic>\n                    mice, associated with intense staining of active Rac1 in glomerular podocytes, but both hypertension and renal injury were ameliorated by NSC23766 and finerenone, associated with Sgk1 inhibition, suggesting that Rac1-MR activation contributes to hypertension and podocyte injury. In conclusion, salt-induced activation of Rac1-MR pathway in distal tubules and glomeruli is involved in DKD progression through hypertension and glomerular injury, respectively. This finding highlights MR antagonism along with Rac1 inhibition as a novel strategy for DKD treatment.\n                  <\/jats:p>","DOI":"10.1161\/hypertensionaha.121.17263","type":"journal-article","created":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T05:03:36Z","timestamp":1622523816000},"page":"82-93","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":55,"title":["Activation of Rac1-Mineralocorticoid Receptor Pathway Contributes to Renal Injury in Salt-Loaded\n                    <i>db\/db<\/i>\n                    Mice"],"prefix":"10.1161","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1885-1263","authenticated-orcid":true,"given":"Daigoro","family":"Hirohama","sequence":"first","affiliation":[{"name":"Division of Clinical Epigenetics, Research Center for Advanced Science and Technology, The University of Tokyo, Japan (D.H., M.N., N.A., W.K., S.O., S.S., T.M., T.F.)."},{"name":"Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan (D.H., W.F., S.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9542-847X","authenticated-orcid":true,"given":"Mitsuhiro","family":"Nishimoto","sequence":"additional","affiliation":[{"name":"Division of Clinical Epigenetics, Research Center for Advanced Science and Technology, The University of Tokyo, Japan (D.H., M.N., N.A., W.K., S.O., S.S., T.M., T.F.)."},{"name":"Department of Internal Medicine, International University of Health and Welfare Mita Hospital, Tokyo, Japan (M.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2703-867X","authenticated-orcid":true,"given":"Nobuhiro","family":"Ayuzawa","sequence":"additional","affiliation":[{"name":"Division of Clinical Epigenetics, Research Center for Advanced Science and Technology, The University of Tokyo, Japan (D.H., M.N., N.A., W.K., S.O., S.S., T.M., T.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1332-8537","authenticated-orcid":true,"given":"Wakako","family":"Kawarazaki","sequence":"additional","affiliation":[{"name":"Division of Clinical Epigenetics, Research Center for Advanced Science and Technology, The University of Tokyo, Japan (D.H., M.N., N.A., W.K., S.O., S.S., T.M., T.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wataru","family":"Fujii","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan (D.H., W.F., S.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeyoshi","family":"Oba","sequence":"additional","affiliation":[{"name":"Division of Clinical Epigenetics, Research Center for Advanced Science and Technology, The University of Tokyo, Japan (D.H., M.N., N.A., W.K., S.O., S.S., T.M., T.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Shibata","sequence":"additional","affiliation":[{"name":"Division of Clinical Epigenetics, Research Center for Advanced Science and Technology, The University of Tokyo, Japan (D.H., M.N., N.A., W.K., S.O., S.S., T.M., T.F.)."},{"name":"Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan (D.H., W.F., S.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Marumo","sequence":"additional","affiliation":[{"name":"Division of Clinical Epigenetics, Research Center for Advanced Science and Technology, The University of Tokyo, Japan (D.H., M.N., N.A., W.K., S.O., S.S., T.M., T.F.)."},{"name":"Department of Pharmacology, School of Medicine, International University of Health and Welfare, Chiba, Japan 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