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Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Nephrotic syndrome (NS) is a common glomerular disease, and podocyte injury is the character of primary NS, usually caused by minimal change disease and membranous nephropathy. Podocytopathy is primarily associated with glomerular proteinuria. Losartan, an angiotensin receptor blocker (ARB), is commonly used in the treatment of NS, and the Angiotensin\u2161 (Ang\u2161)\u2013transient receptor potential ion channel 6 (TRPC6) axis has been reported to act on podocytes to regulate proteinuria in NS. Therefore, the purpose of this study was to explore the relationship in between Ang\u2161\u2013TRPC6, podocyte injury, and proteinuria based on the adriamycin (ADR) NS rat model.<\/jats:p><jats:p><jats:bold>Method:<\/jats:bold> All male rats were divided into three groups: control group, model group, and ARB group. The rats in the model group were induced by ADR, and the rats in the ARB group received losartan after induction of renal injury for 4\u00a0weeks. The changes in parameters related to renal dysfunction, and glomerular and podocyte structural damage, such as Ang\u2161, Ang\u2161 type I receptor (AT1R), TRPC6, CaN, Caspase-3, Nephrin, and Podocin, were analyzed. Furthermore, the kidneys were isolated for study <jats:italic>via<\/jats:italic> transmission electron microscopy (TEM), immunohistochemistry, and western blot (WB) after the rats were sacrificed. <jats:italic>In vitro<\/jats:italic>, immortalized mouse MPC5 podocytes were used to investigate the regulatory effect of flufenamic acid (Flu) and SAR7334 (SAR) on the Ang\u2161-TRPC6 signaling axis. Flow cytometry and WB were conducted to determine the relationship between podocyte injury and Ang\u2161-TRPC6.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold><jats:italic>In vivo<\/jats:italic> results showed that NS rats developed massive albuminuria and abnormal renal function, accompanied by abnormally increased levels of Ang\u2161, TRPC6, AT1R, and CaN and a decreased expression of actin molecules in podocytes, extensive fusion of foot processes (FP), loss of glomerular structural integrity, collapse of podocyte structure, and skeletal reorganization. <jats:italic>In vitro<\/jats:italic> experiments indicated that both Ang\u2161 and Flu (the specific agonist of TRPC6) stimulated the expressions of TRPC6, AT1R, and Caspase-3 in podocytes. The Ang\u2161 receptor\u2013blocker losartan and TRPC6-specific inhibitor SAR blocked the overexpression of the aforementioned proteins. In addition, SAR also attenuated the degradation of podocyte structural proteins and inhibited the fluorescence intensity of intracellular calcium (Ca<jats:sup>2+<\/jats:sup>) and cell apoptosis.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> The involvement of Ang\u2161 in the occurrence of NS proteinuria may be related to podocyte injury induced by activated TRPC6.<\/jats:p>","DOI":"10.3389\/fphar.2022.915153","type":"journal-article","created":{"date-parts":[[2022,8,3]],"date-time":"2022-08-03T05:12:36Z","timestamp":1659503556000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Activation of TRPC6 by Ang\u2161 Induces Podocyte Injury and Participates in Proteinuria of Nephrotic Syndrome"],"prefix":"10.3389","volume":"13","author":[{"given":"Ye","family":"Feng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manman","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunlai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mo","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaoxiang","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dengke","family":"Yin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zihua","family":"Xuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"F783","DOI":"10.1152\/ajprenal.1987.253.5.F783","article-title":"Structure and Development of the Glomerular Capillary Wall and Basement Membrane","volume":"253","author":"Abrahamson","year":"1987","journal-title":"Am. 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