{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T12:25:17Z","timestamp":1782390317654,"version":"3.54.5"},"reference-count":53,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T00:00:00Z","timestamp":1750896000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH NIDDK","award":["R01 DK123264"],"award-info":[{"award-number":["R01 DK123264"]}]},{"name":"NIH NIDDK","award":["037122"],"award-info":[{"award-number":["037122"]}]},{"name":"Arkansas Bioscience Institute","award":["R01 DK123264"],"award-info":[{"award-number":["R01 DK123264"]}]},{"name":"Arkansas Bioscience Institute","award":["037122"],"award-info":[{"award-number":["037122"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Chronic kidney disease (CKD) is twice as prevalent in individuals with obesity-associated non-alcoholic fatty liver disease (Ob-NAFLD), highlighting the need to determine the link and mechanisms of kidney injury as well as explore therapies. Metformin, a first-line treatment for type 2 diabetes, shows promise in managing NAFLD, but its renal benefits in Ob-NAFLD remain unclear. This study investigates the impact of Ob-NAFLD on kidney injury and assesses the potential protective effects of metformin. Methods: Five-week-old female Zucker rats (obese fa\/fa and lean Fa\/Fa) were fed an AIN-93G diet for 8 weeks to induce Ob-NAFLD, then fed the diet with Metformin for 10 weeks. Kidneys were collected for histopathological and biochemical analyses. Results: Histopathological studies showed increased tubular injury, mesangial matrix expansion, and fibrosis in kidneys with Ob-NAFLD compared to lean control (LC) rats. Immunohistochemistry further revealed an elevated macrophage and neutrophil infiltration and increased levels of nitrotyrosine and p22phox in Ob-NAFLD kidneys. Furthermore, Ob-NAFLD rat kidneys showed upregulation of TNF-\u03b1 and CCL2 genes and increased levels of caspase-3 (total and cleaved). Interestingly, metformin treatment significantly decreased TNF-\u03b1 mRNA and blunted nitrotyrosine levels, and modestly reduced immune cell infiltration in Ob-NAFLD. Conclusions: These findings indicate that Ob-NAFLD promotes CKD as evidenced by tubular injury, oxidative stress, inflammation, and fibrosis. While short-term metformin treatment showed anti-oxidative and anti-inflammatory effects in Ob-NAFLD, its impact on structural kidney damage was limited, highlighting the need for longer treatment or alternative therapeutics such as oxidant scavengers and anti-inflammatory drugs to effectively mitigate renal pathologies.<\/jats:p>","DOI":"10.3390\/nu17132115","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T03:39:59Z","timestamp":1750909199000},"page":"2115","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Obesity-Associated NAFLD Coexists with a Chronic Inflammatory Kidney Condition That Is Partially Mitigated by Short-Term Oral Metformin"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2860-7790","authenticated-orcid":false,"given":"Amod","family":"Sharma","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4829-8478","authenticated-orcid":false,"given":"Reza","family":"Hakkak","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"},{"name":"Department of Dietetics and Nutrition, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"},{"name":"Arkansas Children\u2019s Research Institute, Little Rock, AR 72202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neriman","family":"Gokden","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neelam","family":"Joshi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3994-5338","authenticated-orcid":false,"given":"Nirmala","family":"Parajuli","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/S0140-6736(20)30045-3","article-title":"Global, regional, and national burden of chronic kidney disease, 1990\u20132017: A systematic analysis for the Global Burden of Disease Study 2017","volume":"395","author":"Bikbov","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S47","DOI":"10.1016\/j.jhep.2014.12.012","article-title":"NAFLD: A multisystem disease","volume":"62","author":"Byrne","year":"2015","journal-title":"J. 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