Loss of Proximal Tubular Sirtuin 6 Aggravates Unilateral Ureteral Obstruction-Induced Tubulointerstitial Inflammation and Fibrosis by Regulation of β-Catenin Acetylation

• Published in: Cells (Basel, Switzerland) Vol. 11; no. 9; p. 1477
• Main Authors: Jin, Jixiu, Li, Wenjia, Wang, Tian, Park, Byung-Hyun, Park, Sung Kwang, Kang, Kyung Pyo
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27.04.2022; MDPI
• Subjects: Acetylation; Aging; Animals; Benzoates; beta Catenin - metabolism; Carcinogenesis; Cell adhesion molecules; Chemokines; Cytokines; Disease Models, Animal; Epigenetics; Experiments; Extracellular matrix; Female; Fibroblasts; Fibrosis; Gene expression; Humans; Inflammation; Inflammation - pathology; Kidney diseases; Kidney Diseases - pathology; kidney fibrosis; Kinases; Laboratories; Macrophages; Male; Mice; NAD; Nephritis - complications; Polyethylene glycol; Proteins; Proximal tubules; Signal transduction; Sirt6; Sirtuins - metabolism; Smad protein; Sulfur Compounds; Surgery; TGF-β1/Smad signaling pathway; Transforming growth factor-b1; Ureteral Obstruction - complications; β-Catenin; United States > US; Germany; TGF-β1/Smad signaling pathway; acetylation; β-catenin; Sirt6; kidney fibrosis
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells11091477

Renal fibrosis is a significant pathologic change associated with progressive kidney disease. Sirt6 is an NAD+-dependent deacetylase and mono-ADP ribosyltransferase known to play diverse roles in the processes attendant to aging, metabolism, and carcinogenesis. However, the role of proximal tubule-specific Sirt6 in renal fibrosis remains elusive. This study investigates the effect of proximal tubule-specific Sirt6 knockdown on unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial inflammation and fibrosis. Renal fibrosis in wild type and PT-Sirt6KO (Sirt6flox/flox; Ggt1-Cre+) mice was induced by UUO surgery. After seven days, histologic examination and Western blot analysis were performed to examine extracellular matrix (ECM) protein expression. We evaluated inflammatory cytokine and cell adhesion molecule expression after ureteral obstruction. The therapeutic effect of Sirt6 activator MDL-800 on UUO-induced tubulointerstitial inflammation and fibrosis was assessed. The loss of Sirt6 in the proximal tubules aggravated UUO-induced tubular injury, ECM deposition, F4/80 positive macrophage infiltration, and proinflammatory cytokine and chemokine expression. Sirt6 activator MDL-800 mitigated UUO-induced renal tubulointerstitial inflammation and fibrosis. In an in vitro experiment, MDL-800 decreases the transforming growth factor (TGF)-β1-induced activation of myofibroblast and ECM production by regulating Sirt6-dependent β-catenin acetylation and the TGF-β1/Smad signaling pathway. In conclusion, proximal tubule Sirt6 may play an essential role in UUO-induced tubulointerstitial inflammation and fibrosis by regulating Sirt6-dependent β-catenin acetylation and ECM protein promoter transcription.