{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T18:27:10Z","timestamp":1788200830444,"version":"build-2803163510"},"reference-count":49,"publisher":"Portland Press Ltd.","issue":"6","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,6,25]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Background: In the kidney glucose is freely filtered by the glomerulus and, mainly, reabsorbed by sodium glucose cotransporter 2 (SGLT2) expressed in the early proximal tubule. Human proximal tubule epithelial cells (PTECs) undergo pathological and fibrotic changes seen in diabetic kidney disease (DKD) in response to elevated glucose. We developed a specific in vitro model of DKD using primary human PTECs with exposure to high D-glucose and TGF-\u03b21 and propose a role for SGLT2 inhibition in regulating fibrosis. Methods: Western blotting was performed to detect cellular and secreted proteins as well as phosphorylated intracellular signalling proteins. qPCR was used to detect CCN2 RNA. Gamma glutamyl transferase (GT) activity staining was performed to confirm PTEC phenotype. SGLT2 and ERK inhibition on high D-glucose, 25 mM, and TGF-\u03b21, 0.75 ng\/ml, treated cells was explored using dapagliflozin and U0126, respectively. Results: Only the combination of high D-glucose and TGF-\u03b21 treatment significantly up-regulated CCN2 RNA and protein expression. This increase was significantly ameliorated by dapagliflozin. High D-glucose treatment raised phospho ERK which was also inhibited by dapagliflozin. TGF-\u03b21 increased cellular phospho SSXS Smad3 serine 423 and 425, with and without high D-glucose. Glucose alone had no effect. Smad3 serine 204 phosphorylation was significantly raised by a combination of high D-glucose+TGF-\u03b21; this rise was significantly reduced by both SGLT2 and MEK inhibition. Conclusions: We show that high D-glucose and TGF-\u03b21 are both required for CCN2 expression. This treatment also caused Smad3 linker region phosphorylation. Both outcomes were inhibited by dapagliflozin. We have identified a novel SGLT2 -ERK mediated promotion of TGF-\u03b21\/Smad3 signalling inducing a pro-fibrotic growth factor secretion. Our data evince support for substantial renoprotective benefits of SGLT2 inhibition in the diabetic kidney.<\/jats:p>","DOI":"10.1042\/bsr20203947","type":"journal-article","created":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T13:13:38Z","timestamp":1621343618000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["High glucose\u2013induced Smad3 linker phosphorylation and CCN2 expression are inhibited by dapagliflozin in a diabetic tubule epithelial cell model"],"prefix":"10.1042","volume":"41","author":[{"given":"Xinlu","family":"Pan","sequence":"first","affiliation":[{"name":"South West Thames Institute for Renal Research, London, SM5 1AA, U.K."},{"name":"St Georges\u2019 University of London, SW17 0RE, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mysore\u00a0K.","family":"Phanish","sequence":"additional","affiliation":[{"name":"South West Thames Institute for Renal Research, London, SM5 1AA, U.K."},{"name":"St Georges\u2019 University of London, SW17 0RE, U.K."},{"name":"Epsom and St Helier Hospitals NHS Trust, SM5 1AA, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah\u00a0L.","family":"Baines","sequence":"additional","affiliation":[{"name":"St Georges\u2019 University of London, SW17 0RE, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3771-4464","authenticated-orcid":false,"given":"Mark\u00a0E.C.","family":"Dockrell","sequence":"additional","affiliation":[{"name":"South West Thames Institute for Renal Research, London, SM5 1AA, U.K."},{"name":"St Georges\u2019 University of London, SW17 0RE, U.K."},{"name":"Epsom and St Helier Hospitals NHS Trust, SM5 1AA, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2021,6,21]]},"reference":[{"key":"2021111620470516700_B1","doi-asserted-by":"crossref","first-page":"6","DOI":"10.3389\/fmed.2020.00199","article-title":"Diabetic kidney disease and COVID-19: the crash of two pandemics","volume":"7","author":"D'Marco","year":"2020","journal-title":"Front. 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