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

Author(s)

Thieme, Karina ^[1] ; Veloso Pereira, Beatriz Maria ^[1] ; da Silva, Karolline S. ^[2] ; Fabre, Nelly T. ^[3] ; Catanozi, Sergio ^[2] ; Passarelli, Marisa ^{[4, 2]} ; Correa-Giannella, Maria Lucia ^{[4, 3]}

Affiliation

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Fisiol & Biofis, Lab Bases Celulares & Mol Fisiol Renal, Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Lab Lipides LIM 10, Fac Med, Hosp Clin HCFMUSP, Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Lab Carboidratos & Radioimunoensaio LIM 18, Fac Med, Hosp Clin HCFMUSP, Sao Paulo, SP - Brazil

^[4] Univ Nove Julho UNINOVE, Programa Posgrad Med, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: Life Sciences; v. 270, APR 1 2021.
• Web of Science Citations: 1

Abstract

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, Col4al, 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. (AU)

• FAPESP's process: 16/15603-0 - Unraveling mechanisms of glycemic control and chronic complications of Diabetes mellitus: contributions to human health
• Grantee: Ubiratan Fabres Machado
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 13/00713-7 - Effects of chronic administration of albumin modified by advanced glycation (age) on liver tissue: characterization of histological, inflammatory and antioxidant profile
• Grantee: Nelly Takashima Fabre
• Support type: Scholarships in Brazil - Master
• FAPESP's process: 12/18724-2 - Advanced glycated albumin and insulin resistance in rats: focus on periepididimal adipose tissue and N-acetylcysteine actions
• Grantee: Karolline Santana da Silva
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/17251-9 - The effects of chronic administration of albumin modified by advanced glycation (AGE) on renal tissue: characterization of the inflammatory, antioxidant and epigenetic profile
• Grantee: Karina Thieme
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 19/10583-0 - Epigenetic regulation of TET and Klotho proteins in Glomerular Disease
• Grantee: Beatriz Maria Veloso Pereira
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 18/00573-4 - The role of DNA (hydroxy)methylation in podocytes dysfunction: epigenetic perspectives for the treatment of Chronic Kidney Disease
• Grantee: Karina Thieme
• Support type: Research Grants - Young Investigators Grants
• FAPESP's process: 12/04831-1 - New players in glycemic control and chronic complications of Diabetes mellitus: preventive and therapeutic perspectives
• Grantee: Ubiratan Fabres Machado
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 16/04591-1 - Non-coding RNAs in diabetic kidney disease
• Grantee: Karina Thieme
• Support type: Scholarships abroad - Research Internship - Post-doctor