Activation of the YAP/KLF5 transcriptional cascade in renal tubular cells aggravates kidney injury

Yang Liu; Yu Wang; Chunhua Xu; Yu Zhang; Yang Wang; Jinzhong Qin; Hui-Yao Lan; Li Wang; Yu Huang; Kingston Kinglun Mak; Zhihua Zheng; Yin Xia

doi:10.1016/j.ymthe.2024.02.031

Activation of the YAP/KLF5 transcriptional cascade in renal tubular cells aggravates kidney injury

Yang Liu, Yu Wang, Chunhua Xu, Yu Zhang, Yang Wang, Jinzhong Qin, Hui-Yao Lan, Li Wang, Yu Huang, Kingston Kinglun Mak^*, Zhihua Zheng^*, Yin Xia^*

^*Corresponding author for this work

Department of Biomedical Sciences

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

12 Citations (Scopus)

Abstract

The Hippo/YAP pathway plays a critical role in tissue homeostasis. Our previous work demonstrated that renal tubular YAP activation induced by double knockout of the upstream Hippo kinases Mst1 and Mst2 (Mst1/2 dKO) promotes tubular injury and renal inflammation under basal conditions. However, the importance of tubular YAP activation remains to be established in injured kidneys in which many other injurious pathways are simultaneously activated. Here, we show that tubular YAP was already activated 6 h after unilateral ureteral obstruction (UUO). Tubular YAP deficiency greatly attenuated tubular cell over-proliferation, tubular injury and renal inflammation induced by UUO or cisplatin. YAP promoted the transcription of the transcription factor KLF5. Consistently, the elevated expression of KLF5 and its target genes in Mst1/2 dKO or UUO kidneys was blocked by ablation of Yap in tubular cells. Inhibition of KLF5 prevented tubular cell over-proliferation, tubular injury and renal inflammation in Mst1/2 dKO kidneys. Therefore, our results demonstrate that tubular YAP is a key player in kidney injury. YAP and KLF5 form a transcriptional cascade, in which tubular YAP activation induced by kidney injury promotes KLF5 transcription. Activation of this cascade induces tubular cell over-proliferation, tubular injury and renal inflammation. © 2024 The American Society of Gene and Cell Therapy.

Original language	English
Pages (from-to)	1526-1539
Journal	Molecular Therapy
Volume	32
Issue number	5
Online published	27 Feb 2024
DOIs	https://doi.org/10.1016/j.ymthe.2024.02.031
Publication status	Published - 1 May 2024

Funding

This work was supported by National Natural Science Foundation of China 82100706 (to C.X.); General Research Funds 14102620, 14112121, and 14108922, Hong Kong Research Grants Council (to Y.X.); Theme-based Research Scheme T12-101/23-N, and RGC Research Fellow Scheme SRFS2021-4S04, Hong Kong Research Grants Council (to Y.H.); Health and Medical Research Funds (HMRF) 05161376, 07180636, and 08190376, Hong Kong Health Bureau (to Y.X.); The Strategic Seed Funding for Collaborative Research Scheme

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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title = "Activation of the YAP/KLF5 transcriptional cascade in renal tubular cells aggravates kidney injury",

abstract = "The Hippo/YAP pathway plays a critical role in tissue homeostasis. Our previous work demonstrated that renal tubular YAP activation induced by double knockout of the upstream Hippo kinases Mst1 and Mst2 (Mst1/2 dKO) promotes tubular injury and renal inflammation under basal conditions. However, the importance of tubular YAP activation remains to be established in injured kidneys in which many other injurious pathways are simultaneously activated. Here, we show that tubular YAP was already activated 6 h after unilateral ureteral obstruction (UUO). Tubular YAP deficiency greatly attenuated tubular cell over-proliferation, tubular injury and renal inflammation induced by UUO or cisplatin. YAP promoted the transcription of the transcription factor KLF5. Consistently, the elevated expression of KLF5 and its target genes in Mst1/2 dKO or UUO kidneys was blocked by ablation of Yap in tubular cells. Inhibition of KLF5 prevented tubular cell over-proliferation, tubular injury and renal inflammation in Mst1/2 dKO kidneys. Therefore, our results demonstrate that tubular YAP is a key player in kidney injury. YAP and KLF5 form a transcriptional cascade, in which tubular YAP activation induced by kidney injury promotes KLF5 transcription. Activation of this cascade induces tubular cell over-proliferation, tubular injury and renal inflammation. {\textcopyright} 2024 The American Society of Gene and Cell Therapy.",

author = "Yang Liu and Yu Wang and Chunhua Xu and Yu Zhang and Yang Wang and Jinzhong Qin and Hui-Yao Lan and Li Wang and Yu Huang and Mak, {Kingston Kinglun} and Zhihua Zheng and Yin Xia",

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T1 - Activation of the YAP/KLF5 transcriptional cascade in renal tubular cells aggravates kidney injury

AU - Liu, Yang

AU - Wang, Yu

AU - Xu, Chunhua

AU - Zhang, Yu

AU - Wang, Yang

AU - Qin, Jinzhong

AU - Lan, Hui-Yao

AU - Wang, Li

AU - Huang, Yu

AU - Mak, Kingston Kinglun

AU - Zheng, Zhihua

AU - Xia, Yin

PY - 2024/5/1

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N2 - The Hippo/YAP pathway plays a critical role in tissue homeostasis. Our previous work demonstrated that renal tubular YAP activation induced by double knockout of the upstream Hippo kinases Mst1 and Mst2 (Mst1/2 dKO) promotes tubular injury and renal inflammation under basal conditions. However, the importance of tubular YAP activation remains to be established in injured kidneys in which many other injurious pathways are simultaneously activated. Here, we show that tubular YAP was already activated 6 h after unilateral ureteral obstruction (UUO). Tubular YAP deficiency greatly attenuated tubular cell over-proliferation, tubular injury and renal inflammation induced by UUO or cisplatin. YAP promoted the transcription of the transcription factor KLF5. Consistently, the elevated expression of KLF5 and its target genes in Mst1/2 dKO or UUO kidneys was blocked by ablation of Yap in tubular cells. Inhibition of KLF5 prevented tubular cell over-proliferation, tubular injury and renal inflammation in Mst1/2 dKO kidneys. Therefore, our results demonstrate that tubular YAP is a key player in kidney injury. YAP and KLF5 form a transcriptional cascade, in which tubular YAP activation induced by kidney injury promotes KLF5 transcription. Activation of this cascade induces tubular cell over-proliferation, tubular injury and renal inflammation. © 2024 The American Society of Gene and Cell Therapy.

AB - The Hippo/YAP pathway plays a critical role in tissue homeostasis. Our previous work demonstrated that renal tubular YAP activation induced by double knockout of the upstream Hippo kinases Mst1 and Mst2 (Mst1/2 dKO) promotes tubular injury and renal inflammation under basal conditions. However, the importance of tubular YAP activation remains to be established in injured kidneys in which many other injurious pathways are simultaneously activated. Here, we show that tubular YAP was already activated 6 h after unilateral ureteral obstruction (UUO). Tubular YAP deficiency greatly attenuated tubular cell over-proliferation, tubular injury and renal inflammation induced by UUO or cisplatin. YAP promoted the transcription of the transcription factor KLF5. Consistently, the elevated expression of KLF5 and its target genes in Mst1/2 dKO or UUO kidneys was blocked by ablation of Yap in tubular cells. Inhibition of KLF5 prevented tubular cell over-proliferation, tubular injury and renal inflammation in Mst1/2 dKO kidneys. Therefore, our results demonstrate that tubular YAP is a key player in kidney injury. YAP and KLF5 form a transcriptional cascade, in which tubular YAP activation induced by kidney injury promotes KLF5 transcription. Activation of this cascade induces tubular cell over-proliferation, tubular injury and renal inflammation. © 2024 The American Society of Gene and Cell Therapy.

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Activation of the YAP/KLF5 transcriptional cascade in renal tubular cells aggravates kidney injury

Abstract

Funding

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TBRS: Single-Cell Multi-Omics Study of Atherosclerotic Vascular Disease: Narrowing the Gap Between Bench and Bedside

SRFS: Systemic Benefits of Physical Activity: Crosstalk between Organs on Signal Transduction from Mechano-stimulation to Metabolism

Cite this

Activation of the YAP/KLF5 transcriptional cascade in renal tubular cells aggravates kidney injury

Abstract

Funding

UN SDGs

RGC Funding Information

Access Output

Other Access Options

Permanent Link

Other Files and Links

Fingerprint

Projects

TBRS: Single-Cell Multi-Omics Study of Atherosclerotic Vascular Disease: Narrowing the Gap Between Bench and Bedside

SRFS: Systemic Benefits of Physical Activity: Crosstalk between Organs on Signal Transduction from Mechano-stimulation to Metabolism

Cite this