{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T10:06:27Z","timestamp":1792317987547,"version":"4.4.0"},"reference-count":52,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2017,9,21]],"date-time":"2017-09-21T00:00:00Z","timestamp":1505952000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100007476","name":"Canadian Diabetes Association","doi-asserted-by":"publisher","award":["OG\u20103\u201013\u20104073\u2010SZ"],"award-info":[{"award-number":["OG\u20103\u201013\u20104073\u2010SZ"]}],"id":[{"id":"10.13039\/100007476","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Angiotensin II type 2 receptor (AT<jats:sub>2<\/jats:sub>R) deficiency in AT<jats:sub>2<\/jats:sub>R knockout (KO) mice has been linked to congenital abnormalities of the kidney and urinary tract; however, the mechanisms by which this occurs are poorly understood. In this study, we examined whether AT<jats:sub>2<\/jats:sub>R deficiency impaired glomerulogenesis and mediated podocyte loss\/dysfunction <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>. Nephrin\u2010cyan fluorescent protein (CFP)\u2010transgenic (Tg) and Nephrin\/AT<jats:sub>2<\/jats:sub>RKO mice were used to assess glomerulogenesis, while wild\u2010type and AT<jats:sub>2<\/jats:sub>RKO mice were used to evaluate maturation of podocyte morphology\/function. Immortalized mouse podocytes (mPODs) were employed for <jats:italic>in vitro<\/jats:italic> studies. AT<jats:sub>2<\/jats:sub>R deficiency resulted in diminished glomerulogenesis in E15 embryos, but had no impact on actual nephron number in neonates. Pups lacking AT<jats:sub>2<\/jats:sub>R displayed features of renal dysplasia with lower glomerular tuft volume and podocyte numbers. <jats:italic>In vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> studies demonstrated that loss of AT<jats:sub>2<\/jats:sub>R was associated with elevated NADPH oxidase 4 levels, which in turn stimulated ectopic hedgehog interacting protein (<jats:italic>Hhip<\/jats:italic>) gene expression in podocytes. Consequently, ectopic Hhip expression activation either triggers caspase\u20103 and p53\u2010related apoptotic processes resulting in podocyte loss, or activates TGF\u03b21\u2013Smad2\/3 cascades and \u03b1\u2010SMA expression to transform differentiated podocytes to undifferentiated podocyte\u2010derived fibrotic cells. We analyzed <jats:italic>HHIP<\/jats:italic> expression in the kidney disease database (Nephroseq) and then validated this using HHIP immunohistochemistry staining of human kidney biopsies (controls versus focal segmental glomerulosclerosis). In conclusion, loss of AT<jats:sub>2<\/jats:sub>R is associated with podocyte loss\/dysfunction and is mediated, at least in part, via augmented ectopic Hhip expression in podocytes. Copyright \u00a9 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.4946","type":"journal-article","created":{"date-parts":[[2017,7,19]],"date-time":"2017-07-19T08:43:45Z","timestamp":1500453825000},"page":"279-293","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["AT<sub>2<\/sub>R deficiency mediated podocyte loss via activation of ectopic hedgehog interacting protein (<i>Hhip<\/i>) gene expression"],"prefix":"10.1002","volume":"243","author":[{"given":"Min\u2010Chun","family":"Liao","sequence":"first","affiliation":[{"name":"Universit\u00e9 de Montr\u00e9al Centre de Recherche du Centre Hospitalier de l'Universit\u00e9 de Montr\u00e9al (CRCHUM), Tour Viger, Montr\u00e9al  Qu\u00e9bec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin\u2010Ping","family":"Zhao","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Montr\u00e9al Centre de Recherche du Centre Hospitalier de 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