{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:39:47Z","timestamp":1791268787246,"version":"4.1.0"},"reference-count":57,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2014,12,15]],"date-time":"2014-12-15T00:00:00Z","timestamp":1418601600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["R01DK092485"],"award-info":[{"award-number":["R01DK092485"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2015,2]]},"abstract":"Background and Purpose<\/jats:title>Mitochondrial dysfunction, triggered by mitochondria permeability transition (MPT<\/jats:styled-content>), has been centrally implicated in the pathogenesis of podocytopathy and involves a multitude of cell signalling mechanisms, among which, glycogen synthase kinase (GSK<\/jats:styled-content>) 3\u03b2 has emerged as the integration point and plays a crucial role. This study aimed to examine the role of GSK3\u03b2<\/jats:styled-content> in podocyte MPT<\/jats:styled-content> and mitochondrial dysfunction.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>The regulatory effect of GSK3\u03b2<\/jats:styled-content> on MPT<\/jats:styled-content> was examined in differentiated podocytes in culture and in a murine model of adriamycin\u2010induced podocytopathy using 4\u2010benzyl\u20102\u2010methyl\u20101,2,4\u2010thiadiazolidine\u20103,5\u2010dione (TDZD<\/jats:styled-content>\u20108), a highly selective small\u2010molecule inhibitor of GSK3\u03b2<\/jats:styled-content>.<\/jats:p><\/jats:sec>Key Results<\/jats:title>TDZD<\/jats:styled-content>\u20108 therapy prominently ameliorated the proteinuria and glomerular sclerosis in mice with adriamycin nephropathy; this was associated with a correction of GSK3\u03b2<\/jats:styled-content> overactivity in the glomerulus and attenuation of podocyte injuries, including foot process effacement and podocyte death. Consistently, in adriamycin\u2010injured podocytes, TDZD<\/jats:styled-content>\u20108 treatment counteracted GSK3\u03b2<\/jats:styled-content> overactivity, improved cell viability and prevented death, concomitant with diminished oxidative stress, improved mitochondrial dysfunction and desensitized MPT<\/jats:styled-content>. Mechanistically, a discrete pool of GSK3\u03b2<\/jats:styled-content> was found in podocyte mitochondria, which interacted with and phosphorylated clyclophilin F<\/jats:styled-content>, a key structural component of the MPT<\/jats:styled-content> pore. TDZD<\/jats:styled-content>\u20108 treatment prevented the GSK3\u03b2<\/jats:styled-content>\u2010controlled phosphorylation and activation of cyclophilin F<\/jats:styled-content>, desensitized MPT<\/jats:styled-content> and alleviated the damage to mitochondria in podocytes induced by adriamycin in vivo<\/jats:italic> and in vitro<\/jats:italic>.<\/jats:p><\/jats:sec>Conclusions and Implications<\/jats:title>Our findings suggest that pharmacological targeting of GSK3\u03b2<\/jats:styled-content> could represent a promising and feasible therapeutic strategy for protecting podocytes against mitochondrial dysfunction induced by oxidative injuries.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12952","type":"journal-article","created":{"date-parts":[[2014,9,29]],"date-time":"2014-09-29T06:24:51Z","timestamp":1411971891000},"page":"895-909","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Pharmacological targeting of GSK3\u03b2<\/scp> confers protection against podocytopathy and proteinuria by desensitizing mitochondrial permeability transition"],"prefix":"10.1111","volume":"172","author":[{"given":"Zhen","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Nephrology Shanghai Tenth People's Hospital, Tongji University School of Medicine Shanghai China"},{"name":"Division of Kidney Disease and Hypertension Department of Medicine Rhode Island Hospital Brown University School of Medicine Providence RI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Nephrology Shanghai Tenth People's Hospital, Tongji University School of Medicine Shanghai China"},{"name":"Division of Kidney Disease and Hypertension Department of Medicine Rhode Island Hospital Brown University School of Medicine Providence RI 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