Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory of Drug Metabolism Research and Evaluation, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Center of Clinical Laboratory, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China.
Arthritis Res Ther. 2024 Mar 9;26(1):64. doi: 10.1186/s13075-024-03292-y.
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.
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.
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.
In summary, we identified the SIAH2-LATS2 axis as an attractive intervention target in LN to alter the resistance to fibrosis.
狼疮肾炎（LN）是系统性红斑狼疮（SLE）最常见的并发症。LN 的治疗选择有限，增加了患者的经济负担。由于纤维化进展导致 LN 患者的肾脏不可逆转损伤，并进一步进展为慢性肾脏病（CKD）和终末期肾脏疾病（ESRD），因此开发新的靶点来预防 LN 纤维化进展可能为 LN 患者提供一种可行的治疗策略。
在这项研究中，我们检查了 LN 肾活检样本（LN：n=8，正常：n=2）和狼疮易感 MRL/lpr 小鼠（每个疾病阶段 n=8）中 YAP 的激活和 LATS2 的下调。通过 Ad-LATS2 原位注射进一步研究了 LATS2 的功能在 LN 小鼠中（每组 n=6 只小鼠）。我们通过 IP-MS 和 co-IP 检查了 SIAH2-LATS2 调节的作用，并在 LN 小鼠中研究了 SIAH2 抑制剂的保护作用。
体内用腺病毒恢复 LATS2 可减轻 LN 小鼠的肾脏纤维化损伤。此外，我们发现 LATS2 被 SIAH2 介导的 K48 泛素化蛋白酶体途径降解，并促进 YAP 激活，从而加重 LN 中的纤维化进展。底物结合域（SBD）的 H150 区域是 SIAH2-LATS2 结合的重要位点。SIAH2 特异性抑制剂维生素 K3 可防止体内 LN 相关的纤维化损伤。
总之，我们确定了 SIAH2-LATS2 轴作为 LN 中改变纤维化耐药性的有吸引力的干预靶点。
