Tubular transcriptional co-activator with PDZ-binding motif protects against ischemic acute kidney injury

Author:

Wu Chia-Lin1234ORCID,Chang Chia-Chu1ORCID,Yang Tao-Hsiang34,Tsai Alexander Charng-Dar34,Wang Jui-Lin4,Chang Chung-Ho3456,Tarng Der-Cherng278910ORCID

Affiliation:

1. Division of Nephrology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan

2. Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

3. Internal Medicine Research Center, Changhua Christian Hospital, Changhua, Taiwan

4. Translational Research Laboratory, Changhua Christian Hospital, Changhua, Taiwan

5. Department of Chemical and Materials Engineering, Tunghai University, Taichung, Taiwan

6. Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County, Taiwan

7. Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

8. Department and Institute of Physiology, National Yang-Ming University, Taipei, Taiwan

9. Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Chiao Tung University, Hsinchu, Taiwan

10. Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan

Abstract

Abstract 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.

Publisher

Portland Press Ltd.

Subject

General Medicine

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