The SIRT6 allosteric activator MDL-800 suppresses calcium oxalate nephrocalcinosis by alleviating inflammatory and renal damage

Lvwen Zhang; Zhenyu Song; Xike Mao; Yuehan Yang; Bingbing Hou; Yang Chen; Zongyao Hao

doi:10.1016/j.intimp.2024.113864

The SIRT6 allosteric activator MDL-800 suppresses calcium oxalate nephrocalcinosis by alleviating inflammatory and renal damage

Int Immunopharmacol. 2024 Dec 19:146:113864. doi: 10.1016/j.intimp.2024.113864. Online ahead of print.

Authors

Lvwen Zhang¹, Zhenyu Song¹, Xike Mao¹, Yuehan Yang¹, Bingbing Hou², Yang Chen³, Zongyao Hao⁴

Affiliations

¹ Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Institute of Urology, Anhui Medical University, Hefei, China; Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei, China.
² Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Institute of Urology, Anhui Medical University, Hefei, China; Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei, China. Electronic address: [email protected].
³ Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Institute of Urology, Anhui Medical University, Hefei, China; Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei, China. Electronic address: [email protected].
⁴ Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China; Institute of Urology, Anhui Medical University, Hefei, China; Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei, China. Electronic address: [email protected].

PMID: 39706044
DOI: 10.1016/j.intimp.2024.113864

Abstract

Kidney stones consist largely of calcium oxalate (CaOx), and induce inflammation and damage to renal tubular epithelial (RTE) cells, leading to CaOx nephrocalcinosis. Sirtuin 6 (SIRT6), a sirtuin family member, is an NAD-dependent deacetylase that has been associated with cell damage and inflammation in various diseases. This study evaluated the efficacy of the novel SIRT6 allosteric agonist MDL-800 in treating CaOx nephrocalcinosis. The data revealed that MDL-800 preconditioning alleviated CaOx crystal-mediated damage in RTE cells by suppressing inflammation, as shown in both cell and animal studies. Furthermore, MDL-800 enhanced SIRT6 deacetylation at H3K9AC. However, MDL-800 pretreatment of SIRT6-knockdown (KD) RTE cells did not protect against CaOx crystal-induced cell damage and inflammation. Mechanistically, MDL-800 markedly downregulated the expression of IL-1β, TNF-α, MCP-1, and IL-6 in mouse kidneys via the TRL4/NF-κB pathway. These data indicated that MDL-800 reduces inflammation and inhibits the TLR4/NF-κB axis by increasing SIRT6-modulated histone deacetylation, thus inhibiting and protecting against inflammatory responses. In summary, MDL-800 modulation of SIRT6-mediated inflammation and renal damage represents a novel strategy for treating CaOx-mediated nephrocalcinosis.

Keywords: Calcium Oxalate; Inflammation; MDL-800; Nephrocalcinosis; Renal damage; SIRT6.