Tubular transcriptional co-activator with PDZ-binding motif protects against ischemic acute kidney injury
| Autor: | Alexander Charng Dar Tsai, Chung Ho Chang, Jui Lin Wang, Chia-Lin Wu, Tao Hsiang Yang, Chia Chu Chang, Der Cherng Tarng |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine p38 mitogen-activated protein kinases Renal cortex Apoptosis IκB kinase urologic and male genital diseases Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Adaptor Proteins Signal Transducing Kidney urogenital system Chemistry Kinase NF-kappa B Acute kidney injury Epithelial Cells General Medicine Acute Kidney Injury medicine.disease Mice Inbred C57BL Kidney Tubules 030104 developmental biology medicine.anatomical_structure Reperfusion Injury 030220 oncology & carcinogenesis Trans-Activators Cancer research Female Signal transduction Signal Transduction |
| Zdroj: | Clinical Science. 134:1593-1612 |
| ISSN: | 1470-8736 0143-5221 |
| Popis: | Transcriptional co-activator with PDZ-binding motif (TAZ) is a key downstream effector of the Hippo tumor-suppressor pathway. The functions of TAZ in the kidney, especially in tubular epithelial cells, are not well-known. To elucidate the adaptive expression, protective effects on kidney injury, and signaling pathways of TAZ in response to acute kidney injury (AKI), we used in vitro (hypoxia-treated human renal proximal tubular epithelial cells [RPTECs]) and in vivo (mouse ischemia–reperfusion injury [IRI]) models of ischemic AKI. After ischemic AKI, TAZ was up-regulated in RPTECs and the renal cortex or tubules. Up-regulation of TAZ in RPTECs subjected to hypoxia was controlled by IκB kinase (IKK)/nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB) signaling. TAZ overexpression attenuated hypoxic and oxidative injury, inhibited apoptosis and activation of p38 and c-Jun N-terminal kinase (JNK) proteins, and promoted wound healing in an RPTEC monolayer. However, TAZ knockdown aggravated hypoxic injury, apoptosis, and activation of p38 and JNK signaling, delayed wound closure of an RPTEC monolayer, and promoted G0/G1 phase cell-cycle arrest. Chloroquine and verteporfin treatment produced similar results to TAZ overexpression and knockdown in RPTECs, respectively. Compared with vehicle-treated mice, chloroquine treatment increased TAZ in the renal cortex and tubules, improved renal function, and attenuated tubular injury and tubular apoptosis after renal IRI, whereas TAZ siRNA and verteporfin decreased TAZ in the renal cortex and tubules, deteriorated renal failure and tubular injury, and aggravated tubular apoptosis. Our findings indicate the renoprotective role of tubular TAZ in ischemic AKI. Drugs augmenting (e.g., chloroquine) or suppressing (e.g., verteporfin) TAZ in the kidney might be beneficial or deleterious to patients with AKI. |
| Databáze: | OpenAIRE |
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