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

Jixiu Jin; Wenjia Li; Tian Wang; Byung-Hyun Park; Sung Kwang Park; Kyung Pyo Kang

doi:10.3390/cells11091477

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

Cells. 2022 Apr 27;11(9):1477. doi: 10.3390/cells11091477.

Authors

Jixiu Jin¹, Wenjia Li¹, Tian Wang¹, Byung-Hyun Park², Sung Kwang Park^{1

3}, Kyung Pyo Kang^{1

3}

Affiliations

¹ Department of Internal Medicine, Research Institute of Clinical Medicine, Jeonbuk National University Medical School, Jeonju 54907, Korea.
² Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju 54907, Korea.
³ Biomedical Research Institute, Jeonbuk National University Hospital, Jeonju 54907, Korea.

Abstract

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 (Sirt6^flox/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.

Keywords: Sirt6; TGF-β1/Smad signaling pathway; acetylation; kidney fibrosis; β-catenin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Animals
Benzoates
Disease Models, Animal
Female
Fibrosis
Humans
Inflammation / pathology
Kidney Diseases* / pathology
Male
Mice
Nephritis* / complications
Sirtuins* / metabolism
Sulfur Compounds
Ureteral Obstruction* / complications
beta Catenin* / metabolism

Substances

Benzoates
MDL-800
Sulfur Compounds
beta Catenin
Sirt6 protein, mouse
SIRT6 protein, human
Sirtuins

Grants and funding

This research was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korean government (MSIT) (NRF-2018R1D1A1B07045790 and NRF-2021R1A2C1004033 to K.P.K.).