Journal Article

Regulator of calcineurin 1 deletion attenuates mitochondrial dysfunction and apoptosis in acute kidney injury through JNK/Mff signaling pathway

Tao, Shengxiang, Peng, Fang-Fang, Li, Ying, Xiao, Jing-Jie, Liu, Qing, Liu, Hui, Yu, Hong, Zhang, Bai-Fang, Zhang, Zhihan, Wang, Shan

2022

Overview

Ischemia-reperfusion (I/R) induced acute kidney injury (AKI), characterized by excessive mitochondrial damage and cell apoptosis, remains a clinical challenge. Recent studies suggest that regulator of calcineurin 1 (RCAN1) regulates mitochondrial function in different cell types, but the underlying mechanisms require further investigation. Herein, we aim to explore whether RCAN1 involves in mitochondrial dysfunction in AKI and the exact mechanism. In present study, AKI was induced by I/R and cisplatin in RCAN1 flox/flox mice and mice with renal tubular epithelial cells (TECs)-specific deletion of RCAN1. The role of RCAN1 in hypoxia-reoxygenation (HR) and cisplatin-induced injury in human renal proximal tubule epithelial cell line HK-2 was also examined by overexpression and knockdown of RCAN1. Mitochondrial function was assessed by transmission electron microscopy, JC-1 staining, MitoSOX staining, ATP production, mitochondrial fission and mitophagy. Apoptosis was detected by TUNEL assay, Annexin V-FITC staining and Western blotting analysis of apoptosis-related proteins. It was found that protein expression of RCAN1 was markedly upregulated in I/R- or cisplatin-induced AKI mouse models, as well as in HR models in HK-2 cells. RCAN1 deficiency significantly reduced kidney damage, mitochondrial dysfunction, and cell apoptosis, whereas RCAN1 overexpression led to the opposite phenotypes. Our in-depth mechanistic exploration demonstrated that RCAN1 increases the phosphorylation of mitochondrial fission factor (Mff) by binding to downstream c-Jun N-terminal kinase (JNK), then promotes dynamin related protein 1 (Drp1) migration to mitochondria, ultimately leads to excessive mitochondrial fission of renal TECs. In conclusion, our study suggests that RCAN1 could induce mitochondrial dysfunction and apoptosis by activating the downstream JNK/Mff signaling pathway. RCAN1 may be a potential therapeutic target for conferring protection against I/R- or cisplatin-AKI.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 13/1 / 13/109 / 13/2 / 13/31 / 13/51 / 13/89 / 14/19 / 14/28 / 14/34 / 38/89 / 64/110 / 692/308 / 692/420 / 82/29 / Acute Kidney Injury - genetics / Acute Kidney Injury - metabolism / Animal models / Animals / Annexin V / Antibodies / Apoptosis / Apoptosis - genetics / Biochemistry / Biomedical and Life Sciences / c-Jun protein / Calcineurin / Cell Biology / Cell Culture / Cisplatin / Cisplatin - adverse effects / Clonal deletion / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Dynamin / Epithelial cells / Humans / Hypoxia / Immunology / Ischemia / JNK protein / Kidneys / Kinases / Life Sciences / MAP Kinase Signaling System / Membrane Proteins - metabolism / Mice / Mitochondria / Mitochondria - metabolism / Mitochondrial Proteins - metabolism / Muscle Proteins - genetics / Muscle Proteins - metabolism / Phenotypes / Phosphorylation / Reperfusion / Signal transduction / Therapeutic targets / Transcription factors / Transcription Factors - metabolism / Transmission electron microscopy / Western blotting