Ponatinib exacerbate renal injury in systemic lupus erythematosus mouse model through PDGFR-PI3K/AKT pathway

被引：1

作者：

Dong, Yixin ^{[1
]}

Wang, Gangan ^{[2
]}

Yan, Xiwei ^{[2
]}

Ye, Wenling ^{[2
]}

Qiao, Xiangyu ^{[1
]}

Deng, Xingyu ^{[1
]}

Ren, Pengju ^{[1
]}

Jia, Chunyu ^{[2
]}

Chen, Gang ^{[2
]}

Zheng, Ke ^{[2
]}

Jiang, Chengyu ^{[1
]}

Li, Xuemei ^{[2
]}

机构：

[1] Chinese Acad Med Sci & Peking Union Med Coll, Inst Basic Med Sci, State Key Lab Common Mech Res Major Dis, Beijing, Peoples R China

[2] Chinese Acad Med Sci & Peking Union Med Coll, Peking Union Med Coll Hosp, Dept Nephrol, Beijing, Peoples R China

来源：

BIOCHEMICAL PHARMACOLOGY | 2024年 / 230卷

基金：

中国国家自然科学基金;

关键词：

Ponatinib; Systemic lupus erythematosus; Tyrosine kinase inhibitors; Nephrotoxicity; Adiponectin; TARGETED THERAPIES; TYROSINE KINASE; ADIPONECTIN; IMATINIB; INHIBITOR; ASSOCIATION; NEPHRITIS; GROWTH; MUTANT;

D O I：

10.1016/j.bcp.2024.116578

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Lupus nephritis (LN) is a common clinical complication of systemic lupus erythematosus (SLE). Proliferative lupus nephritis represents the gravest form of LN, and since effective drugs for its treatment are still lacking, tyrosine kinase inhibitors (TKIs) find extensive clinical utility due to their notable impact on suppressing cell proliferation and may serve as potential drugs for LN treatment. However, previous studies on the effects of TKI on LN have been controversial. Ponatinib, a third-generation TKI, lacks studies on its role in LN. This study aimed to investigate the impact of the ponatinib on LN. MRL/lpr mice were evaluated for renal function, autoimmune markers and histopathological changes after oral administration of ponatinib. RNA-seq analysis was performed to explore the molecular pathways involved in ponatinib-induced kidney injury. Ponatinib uniquely exacerbated renal damage in MRL/lpr mice, evidenced by a decline in renal function and acute pathological changes, without affecting lupus-related autoimmune markers. Differential expressed genes analysis and functional enrichment implicate ponatinib-induced renal damage in MRL/lpr mice associated with adiponectin. Furthermore, we verified ponatinib signaling the PI3K/AKT pathway through PDGFR alpha, potentially influencing high molecular weight adiponectin (HMW ADIPOQ) expression and exacerbating renal damage. In conclusion, this study demonstrates that ponatinib can up-regulate HMW ADIPOQ expression via the PI3K/AKT pathway by inhibiting PDGFR alpha phosphorylation, highlighting the potential nephrotoxic effects of ponatinib in lupus-prone mice, and underscoring the importance of monitoring renal function in systemic autoimmune diseases patients receiving ponatinib.

引用

页数：13

共 47 条

[1] Renal Toxicities of Targeted Therapies [J].