{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T20:44:12Z","timestamp":1791924252087,"version":"4.3.4"},"reference-count":52,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T00:00:00Z","timestamp":1736985600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"National Science Centre, Poland","doi-asserted-by":"publisher","award":["2018\/29\/B\/NZ4\/02074"],"award-info":[{"award-number":["2018\/29\/B\/NZ4\/02074"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Microalbuminuria is the earliest clinical abnormality in diabetic kidney disease. High glucose (HG) concentrations are associated with the induction of oxidative stress in podocytes, leading to disruption of the glomerular filtration barrier. Our recent study revealed a significant decrease in the membrane-bound fraction of Klotho in podocytes that were cultured under HG conditions. Given that disintegrin and metalloproteinase 17 (ADAM17) is responsible for the shedding of Klotho from the cell membrane, the present study investigated the impact of HG on the interplay between ADAM17 and Klotho in human podocytes. We demonstrated that ADAM17 protein levels significantly increased in urine, renal tissue, and glomeruli from diabetic rats, with a concomitant increase in glomerular albumin permeability. High glucose increased ADAM17 extracellular activity, NADPH oxidase activity, and albumin permeability in podocytes. These effects were reversed after treatment with ADAM17 inhibitor, in cells with downregulated ADAM17 expression, or after the addition of Klotho. Additionally, elevations of extracellular ADAM17 activity were observed in podocytes with the downregulation of Klotho expression. Our data indicate a novel mechanism whereby hyperglycemia deteriorates podocyte function via ADAM17 activation. We also demonstrated the ability of Klotho to protect podocyte function under hyperglycemic conditions in an ADAM17-dependent manner.<\/jats:p>","DOI":"10.3390\/ijms26020731","type":"journal-article","created":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T09:58:36Z","timestamp":1737021516000},"page":"731","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Involvement of ADAM17-Klotho Crosstalk in High Glucose-Induced Alterations of Podocyte Function"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6242-0324","authenticated-orcid":false,"given":"Dorota","family":"Rogacka","sequence":"first","affiliation":[{"name":"Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 80-308 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7691-8243","authenticated-orcid":false,"given":"Patrycja","family":"Rachubik","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 80-308 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9687-1016","authenticated-orcid":false,"given":"Marlena","family":"Typiak","sequence":"additional","affiliation":[{"name":"Department of General and Medical Biochemistry, Faculty of Biology, University of Gdansk, 80-309 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Kulesza","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 80-308 Gdansk, Poland"},{"name":"Laboratory of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, 80-210 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irena","family":"Audzeyenka","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 80-308 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9808-4518","authenticated-orcid":false,"given":"Moin A.","family":"Saleem","sequence":"additional","affiliation":[{"name":"Bristol Renal, University of Bristol, Dorothy Hodgkin Building, Bristol BS1 3NY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7292-3125","authenticated-orcid":false,"given":"Honorata","family":"Sikora","sequence":"additional","affiliation":[{"name":"Department of Biomedical Chemistry, Faculty of Chemistry, University of Gdansk, 80-308 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Gruba","sequence":"additional","affiliation":[{"name":"Department of Environmental Technology, Faculty of Chemistry, University of Gdansk, 80-308 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2216-5597","authenticated-orcid":false,"given":"Magdalena","family":"Wysocka","sequence":"additional","affiliation":[{"name":"Department of Biomedical Chemistry, Faculty of Chemistry, University of Gdansk, 80-308 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8335-3431","authenticated-orcid":false,"given":"Adam","family":"Lesner","sequence":"additional","affiliation":[{"name":"Department of Environmental Technology, Faculty of Chemistry, University of Gdansk, 80-308 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0086-7777","authenticated-orcid":false,"given":"Agnieszka","family":"Piwkowska","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 80-308 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1159\/000072917","article-title":"Podocyte biology and the emerging understanding of podocyte diseases","volume":"23","author":"Barisoni","year":"2003","journal-title":"Am. 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