Proenkephalin-A secreted by renal proximal tubules functions as a brake in kidney regeneration

Chi Liu (), Xiaoliang Liu, Zhongwei He, Jiangping Zhang, Xiaoqin Tan, Wenmin Yang, Yunfeng Zhang, Ting Yu, Shuyi Liao, Lu Dai, Zhi Xu, Furong Li, Yinghui Huang () and Jinghong Zhao ()
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Chi Liu: Army Medical University (Third Military Medical University)
Xiaoliang Liu: Army Medical University (Third Military Medical University)
Zhongwei He: Army Medical University (Third Military Medical University)
Jiangping Zhang: Army Medical University (Third Military Medical University)
Xiaoqin Tan: Army Medical University (Third Military Medical University)
Wenmin Yang: Army Medical University (Third Military Medical University)
Yunfeng Zhang: Army Medical University (Third Military Medical University)
Ting Yu: Army Medical University (Third Military Medical University)
Shuyi Liao: Army Medical University (Third Military Medical University)
Lu Dai: Army Medical University (Third Military Medical University)
Zhi Xu: Army Medical University (Third Military Medical University)
Furong Li: Army Medical University (Third Military Medical University)
Yinghui Huang: Army Medical University (Third Military Medical University)
Jinghong Zhao: Army Medical University (Third Military Medical University)

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Organ regeneration necessitates precise coordination of accelerators and brakes to restore organ function. However, the mechanisms underlying this intricate molecular crosstalk remain elusive. In this study, the level of proenkephalin-A (PENK-A), expressed by renal proximal tubular epithelial cells, decreases significantly with the loss of renal proximal tubules and increased at the termination phase of zebrafish kidney regeneration. Notably, this change contrasts with the role of hydrogen peroxide (H2O2), which acts as an accelerator in kidney regeneration. Through experiments with penka mutants and pharmaceutical treatments, we demonstrate that PENK-A inhibits H2O2 production in a dose-dependent manner, suggesting its involvement in regulating the rate and termination of regeneration. Furthermore, H2O2 influences the expression of tcf21, a vital factor in the formation of renal progenitor cell aggregates, by remodeling H3K4me3 in renal cells. Overall, our findings highlight the regulatory role of PENK-A as a brake in kidney regeneration.

Date: 2023
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DOI: 10.1038/s41467-023-42929-5

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