A novel role of snail in regulating tuberin/AMPK pathways to promote renal fibrosis in the new mouse model of type II diabetes

Sitai Liang, Mukesh Yadav, Kristine S. Vogel, Samy L. Habib

Research output: Contribution to journalArticlepeer-review

Abstract

Epithelial–mesenchymal transition (EMT) plays an important role in tissue fibrosis following chronic exposure to hyperglycemia. This study investigates the role of chronic diabetes in regulating tuberin/snail/AMPK to enhance EMT and increase renal fibrosis. A new mouse model of db/db/TSC2+/− was generated by backcrossing db/db mice and TSC2+/− mice. Wild type (WT), db/db, TSC2+/− and dbdb/TSC2+/− mice were sacrificed at ages 6 and 8 months old. Tuberin protein level was significantly decreased in kidneys from diabetic compared to WT mice at both ages. In addition, tuberin and E-cadherin protein levels were significantly decreased in dbdb/TSC2+/− compared to TSC2+/− and db/db mice. In contrast, p-PS6K, NFkB, snail, vimentin, fibronectin, and α-SMA protein levels were significantly increased in dbdb/TSC2+/− compared to db/db and TSC2+/− mice at ages 6 and 8 months. Both downregulation of AMPK by DN-AMPK and downregulation of tuberin by siRNA resulted in increased NFkB, snail, and fibronectin protein expression and decreased E-cadherin protein expression in mouse primary renal proximal tubular cells. Interestingly, downregulation of snail by siRNA increased tuberin expression via feedback through activation of AMPK and reversed the expression of epithelial proteins such as E-cadherin as well as mesenchymal proteins such as fibronectin, NF-KB, vimentin, and α-SMA in mouse primary renal proximal tubular cells isolated from kidneys of four mice genotypes. The data show that chronic diabetes significantly decreases tuberin expression and that provides strong evidence that tuberin is a major key protein involved in regulating EMT. These data also demonstrated a novel role for snail in regulating of AMPK/tuberin to enhance EMT and renal cell fibrosis in diabetes.

Original languageEnglish (US)
Pages (from-to)730-743
Number of pages14
JournalFASEB BioAdvances
Volume3
Issue number9
DOIs
StatePublished - Sep 2021

Keywords

  • AMPK
  • EMT
  • NFkb
  • diabetes
  • fibronectin
  • snail
  • tuberin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Cancer Research
  • Molecular Medicine
  • Physiology

Fingerprint

Dive into the research topics of 'A novel role of snail in regulating tuberin/AMPK pathways to promote renal fibrosis in the new mouse model of type II diabetes'. Together they form a unique fingerprint.

Cite this