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Investigating the Cytoprotective Mechanisms of the Tardigrade Damage Suppressor (Dsup) Protein in Human Cells Under Hypoxic Stress

ABSTRACT: Introduction: Ischemia/reperfusion injury (IRI) is a common damage due to the restoration of blood flow after an ischemic insult. The pathogenesis of IRI is mainly linked to the production of ROS which sustain cell damage and ultimately promote cell death. The tardigrade damage suppressor protein (Dsup) is a DNA-binding protein that enables tardigrades to tolerate stress conditions including oxidative stress. Aim: We aim to investigate the ability of the tardigrade-derived Damage Suppressor (Dsup) protein to protect human cells from IRI, using an in vitro model of hypoxia and reoxygenation. Methods: The protective role of the tardigrade Dsup protein against ischemia-reperfusion injury was studied in transfected HEK293T cells. We analyzed cell viability, oxidative stress, and the expression of antioxidant proteins using functional assays, proteomics, and Western Blotting. Results: Dsup expression significantly enhanced cell survival following hypoxia-reoxygenation and markedly reduced intracellular ROS levels. Proteomic and Western Blot analyses revealed a significant upregulation of antioxidant enzymes in Dsup-expressing cells. Furthermore, Dsup modulated autophagy and key stress-related pathways, including the MAPK cascade. Dsup remained cytoplasmic under all conditions, and its expression was notably increased by hypoxic stimulus. Conclusion: This study demonstrate that Dsup protects human cells from ischemia-reperfusion injury by reducing oxidative stress and modulating key cytoprotective pathways. Our results establish Dsup as a promising candidate for future therapeutic applications against IRI, meriting further exploration in in vivo models.

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ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Enxhi Shaba

LAB HEAD: Prof. Claudia Landi

PROVIDER: PXD067125 | Pride | 2025-11-24

REPOSITORIES: Pride

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Investigating the Cytoprotective Mechanisms of the Tardigrade Damage Suppressor (Dsup) Protein in Human Cells Under Hypoxic Stress.

Shaba Enxhi E Ricci Claudia C Vantaggiato Lorenza L Paolocci Maria Francesca MF Regoli Tommaso T Miedviedieva Kateryna K Brunetti Jlenia J Ciccone Valerio V Cecchin Claudia C Donnini Sandra S Marzocchi Carlotta C Landi Claudia C Cantara Silvia S

International journal of molecular sciences 20251028 21

Ischemia/reperfusion injury (IRI) is a common damage due to the restoration of blood flow following an ischemic injury. Its pathogenesis is mainly linked to the production of reactive oxygen species (ROS), which sustain cell damage and promote cell death. The tardigrade damage suppressor protein (Dsup) is a DNA-binding protein that enables tardigrades to tolerate stress conditions, including oxidative stress. We investigated the ability of the Dsup to protect human cells from IRI, using an in vi ...[more]

PMID: 41226490

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Project description:Purpose: Acute kidney injury (AKI) is defined as a sudden event of kidney failure or kidney damage occurring within a short period. Ischemia-reperfusion injury (IRI) is a critical factor to induce severe AKI and end-stage kidney disease in the kidney. However, biological mechanisms of ischemia and reperfusion are not well elucidated due to its complex pathophysiological processes. We aim to investigate key biological pathways affected by ischemia and by reperfusion separately at the transcriptome level. Method: We analyzed steady-state gene expressions using RNA-seq transcriptome data for normal (pre-ischemia), ischemia and reperfusion conditions obtained from the human kidney tissue. A conventional differential expression analysis and self-organizing map (SOM) clustering analysis followed by pathway analysis were performed to identify the underlying biological mechanisms of ischemia and reperfusion. Results: Differential expression analysis showed that metabolism and gap junction-related pathways were dysregulated in ischemia, whereas hypertrophy and immune response-related pathways were dysregulated in reperfusion. In addition, SOM clustering analysis revealed that metabolism, apoptosis, and fibrosis-related pathways were significantly dysregulated by ischemia compared to pre-ischemia. On the other hand, cell growth, migration, and immune response-related pathways were highly dysregulated by reperfusion after ischemia. Pro-apoptotic genes and death receptors were down-regulated during ischemia, indicating a protective process against ischemic injury. Reperfusion induced alteration of genes associated with immune components such as B-cell, neutrophil, and interleukin-15. Additionally, genes related to cell growth and migration such as AKT, KRAS, and Rho signaling were down-regulated, which might imply injury responses during reperfusion. Semaphorin 4D and plexin B1 were also down-regulated. However, further investigations are needed to identify their roles. Conclusion: We showed that specific biological pathways were distinctively involved in ischemia and reperfusion during IRI, suggesting that condition-specific therapeutic strategies may be required to prevent severe kidney damage after IRI in clinical research.

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