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논문분류	춘계학술대회 초록집
제목	Protective effects of selective Sirt6 activator, MDL-811 on murine lupus nephritis model
저자	Kyung Pyo Kang
출판정보	2026; 2026(1):
키워드	Sirt6, lupus nephritis, proximal tubular epithelial cells, tubulointerstitial inflammation, ; type I interferon–STAT1 signaling
초록	Objectives: 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. Methods: 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. Results: 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. Conclusion: Our study demonstrates that proximal tubular Sirt6 limits lupus-related kidney injury and intrarenal inflammatory signaling in LN. Furthermore, Sirt6 activation via MDL-811 may serve as a promising adjunctive strategy to complement current immunosuppressive regimens, by targeting the IFN pathway and systemic autoimmunity
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