Chronic advanced-glycation end products treatment induces TXNIP expression and epigenetic changes in glomerular podocytes in vivo and in vitro

• Published in: Life sciences (1973) 2021-04, Vol.270, p.118997, Article 118997
• Main Authors: Thieme, Karina, Pereira, Beatriz Maria Veloso, da Silva, Karolline S., Fabre, Nelly T., Catanozi, Sérgio, Passarelli, Marisa, Correa-Giannella, Maria Lucia
• Format: Article
• Language: English
• Subjects: Acetylcysteine; Advanced glycosylation end products; Age; Animals; Antioxidants; Antioxidants - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - metabolism; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Epigenesis, Genetic - genetics; Epigenetics; Epithelial Cells - metabolism; Gene Expression - genetics; Gene Expression Regulation - drug effects; Glycation End Products, Advanced - metabolism; Glycation End Products, Advanced - pharmacology; Glycosylation; H3K27me3; Histones; Inflammation; Kidney - cytology; Kidney - metabolism; Kidney diseases; Kidney Glomerulus - metabolism; Kidneys; Male; Membrane Proteins; Mesenchyme; MiR-29a; Nephropathy; NOX4 protein; Oxidants; Oxidative Stress; Oxidizing agents; Podocytes; Podocytes - metabolism; Proteins; Proteinuria; Rats; Rats, Wistar; Reactive Oxygen Species - metabolism; Thioredoxin; Transforming growth factor-b1
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2020.118997

Advanced glycation end products (AGEs) play an important role in oxidative stress and inflammation, processes implicated in the development and progression of kidney dysfunction. In the present study, we investigated the participation of the pro-oxidant protein thioredoxin-interacting protein (TXNIP) and of epigenetic mechanisms on kidney tissue (in vivo, in non-diabetic rats) and on terminally differentiated glomerular podocytes (in vitro) chronically exposed to AGEs. AGEs induced total kidney and glomerular TXNIP expression and decreased H3K27me3 content. Concomitant treatment with the antioxidant N-acetyl-cysteine (NAC) reversed only the increased TXNIP expression. TXNIP expression positively correlated with proteinuria and negatively correlated with H3K27me3 content. In vitro studies in podocytes showed that 72 h exposure to AGEs decreased nephrin expression and increased Txnip, Nox4, Col4a1, and epithelial-to-mesenchymal transition (EMT) markers (Acta2, Snail1, and Tgfb1). Podocytes treatment with NAC reversed Nox4, Col4a1, Acta2, and Tgfb1 increased expression but did not abrogate the reduced expression of nephrin. MiR-29a expression was downregulated by AGEs in vivo, but not in vitro. In conclusion, treatment of non-diabetic rats with AGEs induced TXNIP expression and decreased the contents of the repressive epigenetic mark H3K27me3 and of miR-29a, potentially driving injury to glomerular filtration barrier and podocytes dysfunction. •AGEs enhanced glomerular TNXIP and decreased H3K27me3 content in nondiabetic rats.•Proteinuria negatively correlated with nephrin expression and H3K27me3 content.•AGEs reduced total kidney miR-29a expression in non-diabetic rats.•AGEs reduced nephrin and increased mesenchymal markers expression in podocytes.