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Arthritis Research & Therapy

Arthritis Research & Therapy

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LATS2 degradation promoted fibrosis damage and rescued by vitamin K3 in lupus nephritis

Published:9 March 2024 DOI: 10.1186/s13075-024-03292-y PMID: 38459604
Chen Cheng,?Hao Yang,?Chan Yang,?Juan Xie,?Jinshen Wang,?Luping Cheng,?Jianfu He,?Honglian Li,?Haoxing Yuan,?Fangfang Guo,?Minmin Li,?Shuwen Liu

Abstract

Background: Lupus nephritis (LN) is the most common complication of systemic lupus erythematosus (SLE). The limited treatment options for LN increase the economic burdens on patients. Because fibrotic progression leads to irreversible renal damage in LN patients and further progresses to chronic kidney disease (CKD) and the end stage of renal disease (ESRD), developing new targets to prevent LN fibrotic progression could lead to a feasible treatment strategy for LN patients.

Methods: In this study, we examined YAP activation and LATS2 downregulation in LN kidney biopsy samples (LN: n?=?8, normal: n?=?2) and lupus-prone MRL/lpr mice (n?=?8 for each disease stage). The function of LATS2 was further investigated by in situ injection of Ad-LATS2 into mice with LN (n?=?6 mice per group). We examined the role of SIAH2-LATS2 regulation by IP-MS and co-IP, and the protective effect of the SIAH2 inhibitor was investigated in mice with LN.

Results: Restoring LATS2 by an adenovirus in vivo alleviated renal fibrotic damage in mice with LN. Moreover, we found that LATS2 was degraded by a K48 ubiquitination-proteasome pathway mediated by SIAH2 and promoted YAP activation to worsen fibrosis progression in LN. The H150 region of the substrate binding domain (SBD) is an important site for SIAH2-LATS2 binding. The SIAH2-specific inhibitor vitamin K3 protected against LN-associated fibrotic damage in vivo.

Conclusion: In summary, we identified the SIAH2-LATS2 axis as an attractive intervention target in LN to alter the resistance to fibrosis.

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Procduct Name CAS Molecular Formula Supplier Price
Menadione 58-27-5 C11H8O2 726 suppliers $5.00-$3162.50
Menadione 58-27-5 C11H8O2 726 suppliers $5.00-$3162.50
Menadione 58-27-5 C11H8O2 726 suppliers $5.00-$3162.50
Menadione 58-27-5 C11H8O2 726 suppliers $5.00-$3162.50

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