Activation of farnesoid X receptor (FXR) induces crystallin zeta expression in mouse medullary collecting duct cells
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MOLECULAR AND GENOMIC PHYSIOLOGY
Activation of farnesoid X receptor (FXR) induces crystallin zeta expression in mouse medullary collecting duct cells Gulzar Alam 1 & Zhilin Luan 1,2,3 & Aneesa Gul 1 & Heyuan Lu 1,2 & Yunfeng Zhou 4 & Xiaoxiao Huo 1 & Yaqing Li 1 & Chunxiu Du 1 & Zhaokang Luo 1 & Haibo Zhang 1 & Hu Xu 1,2,3 & Feng Zheng 1,3 & Youfei Guan 1,2,3 & Xiaoyan Zhang 1,2,3 Received: 24 March 2020 / Revised: 24 August 2020 / Accepted: 28 August 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords Crystallin . Nuclear receptor . FXR . Oxidative stress . Gene knockout Gulzar Alam and Zhilin Luan contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00424-020-02456-4) contains supplementary material, which is available to authorized users. * Youfei Guan [email protected] * Xiaoyan Zhang [email protected] 1
Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China
2
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
3
Da
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