{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T03:21:05Z","timestamp":1776914465356,"version":"3.51.2"},"reference-count":41,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T00:00:00Z","timestamp":1655683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft (DFG)","award":["GO766\/18-2"],"award-info":[{"award-number":["GO766\/18-2"]}]},{"name":"Deutsche Forschungsgemeinschaft (DFG)","award":["GO 766\/12-3"],"award-info":[{"award-number":["GO 766\/12-3"]}]},{"name":"Deutsche Forschungsgemeinschaft (DFG)","award":["SFB 1365"],"award-info":[{"award-number":["SFB 1365"]}]},{"name":"Deutsche Forschungsgemeinschaft (DFG)","award":["NU 53\/12-2"],"award-info":[{"award-number":["NU 53\/12-2"]}]},{"name":"Deutsche Forschungsgemeinschaft (DFG)","award":["TRR 152"],"award-info":[{"award-number":["TRR 152"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Metabolic syndrome is a significant worldwide public health challenge and is inextricably linked to adverse renal and cardiovascular outcomes. The inhibition of the transient receptor potential cation channel subfamily C member 6 (TRPC6) has been found to ameliorate renal outcomes in the unilateral ureteral obstruction (UUO) of accelerated renal fibrosis. Therefore, the pharmacological inhibition of TPRC6 could be a promising therapeutic intervention in the progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome. In the present study, we hypothesized that the novel selective TRPC6 inhibitor SH045 (larixyl N-methylcarbamate) ameliorates UUO-accelerated renal fibrosis in a New Zealand obese (NZO) mouse model, which is a polygenic model of metabolic syndrome. The in vivo inhibition of TRPC6 by SH045 markedly decreased the mRNA expression of pro-fibrotic markers (Col1\u03b11, Col3\u03b11, Col4\u03b11, Acta2, Ccn2, Fn1) and chemokines (Cxcl1, Ccl5, Ccr2) in UUO kidneys of NZO mice compared to kidneys of vehicle-treated animals. Renal expressions of intercellular adhesion molecule 1 (ICAM-1) and \u03b1-smooth muscle actin (\u03b1-SMA) were diminished in SH045- versus vehicle-treated UUO mice. Furthermore, renal inflammatory cell infiltration (F4\/80+ and CD4+) and tubulointerstitial fibrosis (Sirius red and fibronectin staining) were ameliorated in SH045-treated NZO mice. We conclude that the pharmacological inhibition of TRPC6 might be a promising antifibrotic therapeutic method to treat progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome.<\/jats:p>","DOI":"10.3390\/ijms23126870","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T01:43:27Z","timestamp":1655775807000},"page":"6870","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["In Vivo Inhibition of TRPC6 by SH045 Attenuates Renal Fibrosis in a New Zealand Obese (NZO) Mouse Model of Metabolic Syndrome"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5114-3824","authenticated-orcid":false,"given":"Zhihuang","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Nephrology\/Intensive Care, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, 10117 Berlin, Germany"},{"name":"Experimental and Clinical Research Center, a Joint Cooperation of the Charit\u00e9\u2014University Medicine Berlin and Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Geriatrics, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2317-2302","authenticated-orcid":false,"given":"Ute","family":"Kr\u00fcgel","sequence":"additional","affiliation":[{"name":"Rudolf Boehm Institute for Pharmacology and Toxicology, Leipzig University, 04107 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Schaefer","sequence":"additional","affiliation":[{"name":"Rudolf Boehm Institute for Pharmacology and Toxicology, Leipzig University, 04107 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tilman","family":"Grune","sequence":"additional","affiliation":[{"name":"Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany"},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site, 10785 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5995-6555","authenticated-orcid":false,"given":"Bernd","family":"N\u00fcrnberg","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Experimental Therapy and Toxicology and Interfaculty Center of Pharmacogenomics and Drug Research, University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"May-Britt","family":"K\u00f6hler","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Research Center, a Joint Cooperation of the Charit\u00e9\u2014University Medicine Berlin and Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maik","family":"Gollasch","sequence":"additional","affiliation":[{"name":"Department of Nephrology\/Intensive Care, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, 10117 Berlin, Germany"},{"name":"Department of Internal Medicine and Geriatrics, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dmitry","family":"Tsvetkov","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Geriatrics, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lajos","family":"Mark\u00f3","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Research Center, a Joint Cooperation of the Charit\u00e9\u2014University Medicine Berlin and Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany"},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site, 10785 Berlin, Germany"},{"name":"Berlin Institute of Health at Charit\u00e9-Universit\u00e4tsmedizin Berlin, 10178 Berlin, Germany"},{"name":"Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, 10117 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/S0140-6736(13)60687-X","article-title":"Chronic kidney disease: Global dimension and perspectives","volume":"382","author":"Jha","year":"2013","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1126\/science.1193032","article-title":"Association of trypanolytic ApoL1 variants with kidney disease in African Americans","volume":"329","author":"Genovese","year":"2010","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4467","DOI":"10.1038\/s41467-020-18304-z","article-title":"DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice","volume":"11","author":"Li","year":"2020","journal-title":"Nat. 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