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journal article·2025-06Open access

Enhancer Profiling Reveals a Protective Role of RXRα Against Calcium Oxalate‐Induced Crystal Deposition and Kidney Injury

Yu Yang, Xudan Dou, Yongzhan Sun, Mengyao Wang, Jing Wang, Xinyi Cao, Haijie Xie, Linguo Xie, Weiping Tian, Jing Nie, Yupeng Chen, Chunyu Liu, Lirong Zhang

Advanced Science· Volume 12· Issue 21
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Abstract

Abstract During the formation of kidney stones, the interaction between crystals and tubular epithelial cells (TECs) leads to tubular injury and dysfunction, which in turn promote stone formation. However, the molecular mechanisms underlying these changes in TECs remain elusive. Drug screening revealed that JQ1 inhibited the adhesion of calcium oxalate (CaOx) crystals to TECs. Its therapeutic effect is further confirmed in a glyoxylic acid‐induced CaOx crystal deposition mouse model. Utilizing epigenomic and transcriptomic profiling, dynamic enhancer landscape and gene expression program associated with nephrolithiasis are charted. Bioinformatic analysis pinpointing the RXRα as a central transcription factor (TF) modulating enhancer activity. Importantly, the animal studies revealed that RXRα deletion promoted the CaOx crystal deposition, while its activation by Bexarotene (Bex), an FDA‐approved drug, mitigated this progression. Mechanistically, under normal circumstances, RXRα inhibited nephrolithiasis‐promoting genes by recruiting the HDAC3/SMART complex to repress enhancer activity. Yet, with the progression of CaOx crystal deposition, RXRα expression decreased, leading to enhancer activation and subsequent upregulation of nephrolithiasis‐promoting genes. In summary, the work illustrates an epigenetic mechanism underlying TECs fate transition during CaOx crystal deposition and highlights the therapeutic potential of JQ1 and Bex in managing kidney stone diseases.
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Research context

Materials processing

OpenAlex topics: Kidney Stones and Urolithiasis Treatments · Chronic Kidney Disease and Diabetes · Renal and related cancers

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Urology Tianjin Institute of Urology The Second Hospital of Tianjin Medical University Tianjin 300211 China

The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) State Key Laboratory of Experimental Hematology Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Medical University Tianjin 300070 China

Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy Xuzhou Medical University Xuzhou Jiangsu 221004 China

Research Center of Basic Medical Sciences Tianjin Medical University Tianjin 300070 China

Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular Disease Department of Cardiology Tianjin Institute of Cardiology The Second Hospital of Tianjin Medical University Tianjin 300211 China

Biobank of Peking University First Hospital Beijing 100034 China

Funding

National Natural Science Foundation of China · Natural Science Foundation of Tianjin Municipality · Tianjin Municipal Education Commission · China Postdoctoral Science Foundation · Innovative Research Group Project of the National Natural Science Foundation of China

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