{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T14:37:16Z","timestamp":1793025436571,"version":"4.5.0"},"reference-count":74,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:00:00Z","timestamp":1790380800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:00:00Z","timestamp":1790380800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["FASEB BioAdvances"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Dapagliflozin, a potent sodium\u2010glucose cotransporter 2 (SGLT2) inhibitor, slows diabetic kidney disease (DKD) progression and reduces blood pressure in diabetic mice, potentially via modulation of tubular sodium transporters and inflammatory pathways. RING\u2010type E3 ligases, including cullin\u2010based complexes, regulate the stability of with\u2010no\u2010lysine kinases (WNK1\/4), key upstream activators of the sodium\u2010potassium\u2010chloride cotransporter 2 (NKCC2). Twelve\u2010week\u2010old male db\/db mice were placed on a high\u2010salt diet to induce hypertension and accelerate DKD, then randomized to receive dapagliflozin or vehicle by oral gavage for 14\u2009days. Metabolic cages were used for 24\u2010h urine collection, and glomerular filtration rate was measured using FITC\u2010sinistrin clearance. Blood pressure was assessed by tail\u2010cuff plethysmography. Kidneys were processed for histology, immunohistochemistry, Western blotting, and label\u2010free proteomics. Dapagliflozin markedly reduced systolic blood pressure and improved renal injury on Periodic acid\u2013Schiff staining, accompanied by reduced lactic acid accumulation and a lower urinary albumin\u2010to\u2010creatinine ratio. Proteomic profiling demonstrated differential abundance of multiple signaling proteins between groups. Western blotting showed increased expression of cullin 1, 2, and 3 family members, with a significant reduction in NKCC2 and aquaporin\u20102 protein levels in dapagliflozin\u2010treated mice. In cultured mouse thick ascending limb cells, dapagliflozin inhibited high glucose\u2013induced activation of the NLRP3 inflammasome, indicating an additional anti\u2010inflammatory effect. Dapagliflozin confers renoprotection in salt\u2010loaded hypertensive db\/db mice by lowering blood pressure, attenuating tubular and glomerular injury, reducing NKCC2 abundance possibly via enhanced cullin\u2010mediated degradation, and attenuating high\u2010glucose\u2013induced NLRP3 protein expression.<\/jats:p>","DOI":"10.1096\/fba.2026-00209","type":"journal-article","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T07:12:32Z","timestamp":1790406752000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dapagliflozin Attenuates\n                    <scp>NKCC2<\/scp>\n                    Protein Expression and Alleviates Diabetic Kidney Disease in Salt Loaded\u2010Hypertensive Diabetic Db\/Db Mice"],"prefix":"10.1096","volume":"8","author":[{"given":"Zenab","family":"Shahzad","sequence":"first","affiliation":[{"name":"Department of Medicine, College of Medicine University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niharika","family":"Bala","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Medicine University of Florida  Gainesville Florida USA"},{"name":"Department of Physiology &amp; Aging, College of Medicine University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arooba","family":"Illyas","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of South Dakota  Vermillion South Dakota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Kazory","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Medicine University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indra","family":"Chandrasekar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of South Dakota  Vermillion South Dakota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4381-1172","authenticated-orcid":false,"given":"Abdel A.","family":"Alli","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Medicine University of Florida  Gainesville Florida USA"},{"name":"Department of Physiology &amp; Aging, College of Medicine University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,26]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22189800"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2019.117090"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1159\/000543336"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00240.2023"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00079.2022"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.96700"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.729334"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0100777"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.14336\/AD.2018.0928"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-016-2402-z"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.200900058"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.123.064346"},{"issue":"12","key":"e_1_2_9_14_1","first-page":"6690","article-title":"Tempol Treatment Normalizes Membrane Expression of Epithelial Transport Proteins in the Kidney of Salt\u2010Loaded Hypertensive Diabetic Db\/Db Mice","volume":"15","author":"Dogan Y. 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