루프스 신염 모델에서 근위세뇨관 Sirt6의 보호효과 연구 = The protective role of proximal tubule Sirt6 in the murine lupus nephritis model

다국어 초록 (Multilingual Abstract)

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease, and lupus nephritis (LN) is a major determinant of long-term renal outcome. Beyond classic glomerular immune complex deposition, remodeling of the intrarenal immune microenvironment and tubulointerstitial inflammation also contribute to LN progression. Sirtuin 6 (Sirt6) is a nuclear deacetylase involved in tissue injury and inflammation, but its role in LN, particularly in proximal tubular cells, remains unclear. Here, we established a lupus-like nephritis model using the TLR7 agonist R848, assessed the effects of Sirt6 loss using wild-type and proximal tubule–specific Sirt6 knockout (PT-Sirt6KO) mice, and evaluated pharmacological activation with the selective Sirt6 activator MDL-811. Renal injury, immune complex deposition, inflammatory cell infiltration, and inflammatory gene expression were evaluated by histology, immunofluorescence, and qPCR, with complementary in vitro studies in LPS-stimulated HK-2 cells. R848-treated PT-Sirt6KO mice showed worsened renal injury, increased glomerular immune complex deposition, and higher expression of inflammatory chemokines, cytokines, and adhesion molecules. In contrast, MDL-811 reduced systemic autoimmunity and renal damage and suppressed inflammatory gene programs. Mechanistically, MDL-811 increased Sirt6 expression and decreased IFN-α–MyD88–STAT1/NF-κB/IRF3 signaling activity and H3K56 acetylation, supporting a protective role for proximal tubular Sirt6 and a rationale for Sirt6 activation as an anti-inflammatory strategy.

목차 (Table of Contents)

• Contents
• Abstract i
• Introduction 1
• Materials and methods 6
• Results 15
• Discussion 26
• Figure legends 31
• Figures 38
• References 48
• Abstract (Korean) 51