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Activation of farnesoid X receptor (FXR) induces crystallin zeta expression in mouse medullary collecting duct cells

  • Molecular and genomic physiology
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Abstract

Crystallin zeta (CRYZ) is a phylogenetically restricted water-soluble protein and provides cytoprotection against oxidative stress via multiple mechanisms. Increasing evidence suggests that CRYZ is high abundantly expressed in the kidney where it acts as a transacting factor in increasing glutaminolysis and the Na+/K+/2Cl– cotransporter (BSC1/NKCC2) expression to help maintain acid–base balance and medullary hyperosmotic gradient. However, the mechanism by which CRYZ is regulated in the kidney remains largely uncharacterized. Here, we show that CRYZ is a direct target of farnesoid X receptor (FXR), a nuclear receptor important for renal physiology. We found that CRYZ was ubiquitously expressed in mouse kidney and constitutively expressed in the cytoplasm of medullary collecting duct cells (MCDs). In primary cultured mouse MCDs, CRYZ expression was significantly upregulated by the activation and overexpression of FXR. FXR-induced CRYZ expression was almost completely abolished in the MCD cells with siRNA-mediated FXR knockdown. Consistently, treatment with FXR agonists failed to induce CRYZ expression in the MCDs isolated from mice with global and collecting duct–specific FXR deficiency. We identified a putative FXR response element (FXRE) on the CRYZ gene promoter. The luciferase reporter and ChIP assays revealed that FXR can bind directly to the FXRE site, which was further markedly enhanced by FXR activation. Furthermore, we found CRYZ overexpression in MCDs significantly attenuated hypertonicity-induced cell death possibly via increasing Bcl-2 expression. Collectively, our findings demonstrate that CRYZ is constitutively expressed in renal medullary collecting duct cells, where it is transcriptionally controlled by FXR. Given a critical role of FXR in MCDs, CRYZ may be responsible for protective effect of FXR on the survival of MCDs under hypertonic condition during dehydration.

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Funding

This work was supported by the National Natural Science Foundation of China Grants 81722010, 81970606 (to X.Z.); 91639201 and 81970595 (to Y.G.); 81601174 (to Z. L.); 81900267 (to H.X.) and the Liaoning BaiQianWan Talents Program.

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  1. Gulzar Alam and Zhilin Luan contributed equally to this work.

Authors and Affiliations

  1. Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China

    Gulzar Alam, Zhilin Luan, Aneesa Gul, Heyuan Lu, Xiaoxiao Huo, Yaqing Li, Chunxiu Du, Zhaokang Luo, Haibo Zhang, Hu Xu, Feng Zheng, Youfei Guan & Xiaoyan Zhang

  2. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China

    Zhilin Luan, Heyuan Lu, Hu Xu, Youfei Guan & Xiaoyan Zhang

  3. Dalian Key Laboratory for Nuclear Receptors in Major Metabolic Diseases, Dalian, 116044, Liaoning, China

    Zhilin Luan, Hu Xu, Feng Zheng, Youfei Guan & Xiaoyan Zhang

  4. Medical Research Center, Department of Physiology at the Basic Medical College, Shenzhen University Health Science Center, Shenzhen, 518060, China

    Yunfeng Zhou

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  1. Gulzar Alam
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Alam, G., Luan, Z., Gul, A. et al. Activation of farnesoid X receptor (FXR) induces crystallin zeta expression in mouse medullary collecting duct cells. Pflugers Arch - Eur J Physiol 472, 1631–1641 (2020). https://doi.org/10.1007/s00424-020-02456-4

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