Abstract
4-Phenylbutyrate (4-PBA), a chemical chaperone known to reduce endoplasmic reticulum (ER) stress—a key contributor to kidney injury and fibrosis—has shown therapeutic potential in various disease models. However, the impact of hindlimb unloading (HU) on renal ER stress and its transcriptomic landscape remains poorly characterized. To our knowledge, this study provides the first comprehensive transcriptomic profiling of HU-induced renal alterations and their modulation by 4-PBA in C57BL/6J mice. To evaluate the protective effects of 4-PBA against HU-induced renal injury, mice were divided into three groups: ground-based controls (GC), HU mice receiving vehicle treatment (HU), and HU mice treated with 4-PBA. Renal histological and molecular alterations were assessed, and RNA sequencing was performed using the Illumina platform to characterize ER stress-related gene expression changes. HU induced significant ER stress-associated protein dysregulation and renal pathological alterations, which were partially attenuated by 4-PBA treatment. Gene Ontology enrichment analysis confirmed elevated ER stress signaling in HU kidneys and its reduction following 4-PBA administration. KEGG and Reactome pathway analyses further demonstrated modulation of multiple ER stress-associated and cytoprotective pathways with 4-PBA treatment. These findings provide transcriptomic-level evidence that 4-PBA mitigates HU-induced renal stress responses and support its potential as a therapeutic strategy for renal dysfunction associated with microgravity, prolonged immobilization, or sedentary conditions.
Data availability
All data generated and analyzed during this study have been deposited in the GEO database NCBI (https://www.ncbi.nlm.nih.gov/geo/), with the accession number: **GSE235042** with a reviewer access token as **ybybakoudpeblkt**.
Abbreviations
- 4-PBA:
-
4-phenyl butyrate
- ARRIVE:
-
Animal Research: Reporting of in Vivo Experiments
- ER:
-
Endoplasmic Reticulum
- GO:
-
GENE Ontology
- HDAC:
-
Histone Deacetylase
- HU:
-
Hindlimb Unloaded
- IGV:
-
Integrative Genomics Viewer
- KEGG:
-
Kyoto Encyclopedia of Genes and Genomes
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Acknowledgements
We would like to acknowledge the financial support through the award of the 4th Forum for Women in Research (QUWA): Sustaining Women’s Empowerment in Research and Innovation at the University of Sharjah sponsored by the Abu Dhabi National Oil Company (ADNOC), Emirates NBD, the Sharjah Electricity Water and Gas Authority (SEWA), the Technology Innovation Institute (TII), and GSK.
Funding
This work was supported by a targeted grant of University of Sharjah (23010901126 and 22010901110).
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AVR, RQ and DGKM conceptualized the study. GVB, JJ, GR, SE and AVR collected the data. AVR, RQ, FA, AK DGKM and GVB did the statistical analysis. AVR did the funding acquisition. AVR, RQ, SE and RQ did the project administration and supervision. AVR, RQ and DGKM did the validation and original draft of the manuscript. AVR, GVB, SE, RQ and DGKM done the review and editing.
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Ranade, A.V., Bernhardt, G.V., Jose, J. et al. 4-Phenylbutyrate mitigates renal pathology linked to ER stress related pathways in C57BL/6J mice with hindlimb unloading. Sci Rep (2026). https://doi.org/10.1038/s41598-026-47754-6
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DOI: https://doi.org/10.1038/s41598-026-47754-6
