{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:56:06Z","timestamp":1760151366509,"version":"build-2065373602"},"reference-count":59,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T00:00:00Z","timestamp":1645747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Background: Recently published research demonstrated direct renoprotective effects of the glucagon-like peptide-1 receptor agonist GLP 1 RA, but the relevant molecular mechanisms are still not clear. The aim of this research was to assess the effects of Liraglutide in a cell culture model of diabetic nephropathy on cell viability, antioxidant (GSH) and transforming growth factor beta 1 (TGF- \u03b21) levels and extracellular matrix (ECM) expression. The metabolic activity in hyperglycemic conditions and the effect of Liraglutide treatment were assessed by measuring Akt, pAkt, GSK3\u03b2, pGSK3\u03b2, pSTAT3, SOCS3, iNOS and NOX4 protein expression with Western blot. F actin distribution was used to assess the structural changes of the cells upon treatment. Materials and methods: The cells were exposed to high glucose (HG30 mM) followed by 0.5 mM H2O2 and a combination of glucose and H2O2 during 24 h. Subsequently, the cells were treated with different combinations of HG30, H2O2 and Liraglutide. Cell viability was determined by an MTT colorimetric test, and the GSH, TGF-\u03b21 concentration and ECM expression were measured using a spectrophotometric\/microplate reader assay and an ELISA kit, respectively. Western blotting was used to detect the protein level of Akt, pAkt, GSK3\u03b2, pGSK3\u03b2, pSTAT3, SOCS3, iNOS and NOX4. The F-actin cytoskeleton was visualized with Phalloidin stain and subsequently quantified. Results: Cell viability was decreased as well as GSH levels in cells treated with a combination of HG30\/H2O2, and HG30 alone (p &lt; 0.001). The addition of Liraglutide improved the viability in cells treated with HG30, but it did not affect the cell viability in the cell treated with the addition of H2O2. GSH increased with the addition of Liraglutide in HG30\/H2O2 (p &lt; 0.001) treated cells, with no effect in cells treated only with HG30. TGF-\u03b21 levels (p &lt; 0.001) were significantly increased in HG30 and HG30\/H2O2. The addition of Liraglutide significantly decreased the TGF-\u03b21 levels (p &lt; 0.01; p &lt; 0.05) in all treated cells. The synthesis of collagen was significantly increased in HG30\/H2O2 (p &lt; 0.001), while the addition of Liraglutide in HG30\/H2O2 significantly decreased collagen (p &lt; 0.001). Akt signaling was not significantly affected by treatment. The GSK3b and NOX4 levels were significantly reduced (p &lt; 0.01) after the peroxide and glucose treatment, with the observable restoration upon the addition of Liraglutide suggesting an important role of Liraglutide in oxidative status regulation and mitochondrial activity. The treatment with Liraglutide significantly upregulated STAT3 (p &lt; 0.01) activity, with no change in SOCS3 indicating a selective regulation of the STAT 3 signaling pathway in glucose and the oxidative overloaded environment. A significant reduction in the distribution of F-actin was observed in cells treated with HG30\/H2O2 (p &lt; 0.01). The addition of Liraglutide to HG30-treated cells led to a significant decrease of distribution of F-actin (p &lt; 0.001). Conclusion: The protective effect of Liraglutide is mediated through the inhibition of TGF beta, but this effect is dependent on the extent of cellular damage and the type of toxic environment. Based on the WB analysis we have revealed the signaling pathways involved in cytoprotective and cytotoxic effects of the drug itself, and further molecular studies in vitro and vivo are required to elucidate the complexity of the pathophysiological mechanisms of Liraglutide under conditions of hyperglycemia and oxidative stress.<\/jats:p>","DOI":"10.3390\/cimb44030072","type":"journal-article","created":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T10:00:40Z","timestamp":1645783240000},"page":"1087-1114","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Renoprotective Effect of Liraglutide Is Mediated via the Inhibition of TGF-Beta 1 in an LLC-PK1 Cell Model of Diabetic Nephropathy"],"prefix":"10.3390","volume":"44","author":[{"given":"Vjera","family":"Nin\u010devi\u0107","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia"},{"name":"Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Crkvena 21, 31000 Osijek, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4076-2942","authenticated-orcid":false,"given":"Milorad","family":"Zjali\u0107","sequence":"additional","affiliation":[{"name":"Department of Medical Biology and Genetics, Faculty of Medicine, J.J. Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tea Omanovi\u0107","family":"Kolari\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia"},{"name":"Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Crkvena 21, 31000 Osijek, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Smoli\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia"},{"name":"Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Crkvena 21, 31000 Osijek, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2523-6007","authenticated-orcid":false,"given":"Tomislav","family":"Kizivat","sequence":"additional","affiliation":[{"name":"Clinical Institute of Nuclear Medicine and Radiation Protection, University Hospital Osijek, 31000 Osijek, Croatia"},{"name":"Department for Nuclear Medicine and Oncology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0079-2349","authenticated-orcid":false,"given":"Lucija","family":"Kuna","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia"},{"name":"Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Crkvena 21, 31000 Osijek, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksandar","family":"V\u010dev","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, Physiology and Immunology, Faculty of Dental Medicine and Health Osijek, J.J. Strossmayer University of Osijek, 31000 Osijek, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashraf","family":"Tabll","sequence":"additional","affiliation":[{"name":"Microbial Biotechnology Department, Genetic Engineering and Biotechnology Research Division, National Research Center, Cairo 12622, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8861-5987","authenticated-orcid":false,"given":"Ines Bili\u0107","family":"\u0106ur\u010di\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia"},{"name":"Department of Diabetes, Endocrinology and Metabolism Disorders, University Hospital Osijek, 31000 Osijek, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1007\/s11892-019-1133-6","article-title":"The Global Burden of Diabetic Kidney Disease: Time Trends and Gender Gaps","volume":"19","author":"Thomas","year":"2019","journal-title":"Curr. 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