MicroRNA-mediated regulation of hypoxic kidney adaptation in naked mole-rats (Heterocephalus glaber)

Yasser Attaie; Sarah A Breedon; Saif Rehman; Mohammad Ojaghi; Karen L Kadamani; Matthew E Pamenter; Kenneth B Storey

doi:10.1016/j.biochi.2026.02.007

MicroRNA-mediated regulation of hypoxic kidney adaptation in naked mole-rats (Heterocephalus glaber)

Biochimie. 2026 Feb 4:244:54-63. doi: 10.1016/j.biochi.2026.02.007. Online ahead of print.

Authors

Yasser Attaie¹, Sarah A Breedon², Saif Rehman², Mohammad Ojaghi³, Karen L Kadamani³, Matthew E Pamenter⁴, Kenneth B Storey²

Affiliations

¹ Institute of Biochemistry and Department of Biology, Carleton University, Ottawa, ON, Canada. Electronic address: yasserattaie@cmail.carleton.ca.
² Institute of Biochemistry and Department of Biology, Carleton University, Ottawa, ON, Canada.
³ Biology Department, University of Ottawa, Ottawa, ON, Canada.
⁴ Biology Department, University of Ottawa, Ottawa, ON, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada.

PMID: 41651162
DOI: 10.1016/j.biochi.2026.02.007

Abstract

MicroRNAs play crucial roles in post-transcriptional regulation during environmental stress, yet their contribution to hypoxia adaptation in naturally hypoxia-tolerant species remains poorly understood. Here, we characterized the miRNA expression profile in kidneys of the naked mole-rat (Heterocephalus glaber), a subterranean rodent renowned for its exceptional hypoxia tolerance. Small RNA from naked-mole rat kidneys was sequenced under normoxic and hypoxic conditions to predict miRNA-mRNA interactions during low-oxygen stress. Bioinformatic analysis identified differentially expressed miRNAs and used pathway enrichment to predict regulatory mechanisms controlling kidney adaptation to hypoxia. Upregulated miRNAs, including let-7c-5p and miR-29a-3p target genes involved in cell cycle progression, extracellular matrix remodeling, and metabolic pathways, corresponding with negative enrichment of these processes. Conversely, downregulated miRNAs relieve inhibition of transcripts involved in chromatin remodeling, RNA processing, and immune signaling, aligning with positive enrichment of these adaptive pathways. Gene Ontology cellular component analysis suggested systematic subcellular reorganization, with suppression of extracellular and secretory compartments and enhancement of nuclear, RNA processing, and cytoskeletal structures. Notably, hypoxia induced upregulation of ribonucleoprotein complexes, spliceosomal machinery, and histone methyltransferase complexes, while downregulating extracellular matrix components and secretory pathway structures. This coordinated miRNA response appears to optimize energy utilization by suppressing non-essential pathways while selectively enhancing survival mechanisms through targeted post-transcriptional control; however further studies are required to confirm these findings. Our findings provide novel insights into the molecular mechanisms underlying the remarkable hypoxia tolerance of naked mole-rats and highlight miRNA-mediated regulation as a key adaptive strategy in mammalian hypoxic survival.