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BMC veterinary research2019; 15(1); 24; doi: 10.1186/s12917-018-1748-x

Detection of endoplasmic reticulum stress and the unfolded protein response in naturally-occurring endocrinopathic equine laminitis.

Abstract: Laminitis is often associated with endocrinopathies that cause hyperinsulinemia and is also induced experimentally by hyperinsulinemia, suggesting that insulin initiates laminitis pathogenesis. Hyperinsulinemia is expected to activate pro-growth and anabolic signaling pathways. We hypothesize that chronic over-stimulation of these pathways in lamellar tissue results in endoplasmic reticulum stress, contributing to tissue pathology, as it does in human metabolic diseases. We tested this hypothesis by asking whether lamellar tissue from horses with naturally-occurring endocrinopathic laminitis showed expression of protein markers of endoplasmic reticulum stress. Results: Three markers of endoplasmic reticulum stress, spliced XBP1, Grp78/BiP and Grp94, were upregulated 2.5-9.5 fold in lamellar tissues of moderately to severely laminitic front limbs (n = 12) compared to levels in controls (n = 6-7) measured by immunoblotting and densitometry. Comparing expression levels between laminitic front limbs and less affected hind limbs from the same horses (paired samples from 7 to 8 individual horses) demonstrated significantly higher expression for both spliced XBP1 and Grp78/BiP in the laminitic front limbs, and a similar trend for Grp94. Expression levels of the 3 markers were minimal in all samples of the control (n = 6-7) or hind limb groups (n = 7-8). Immunofluorescent localizations were used to identify cell types expressing high levels of Grp78/BiP, as an indicator of endoplasmic reticulum stress. Grp78/BiP expression was highly elevated in suprabasal epidermal keratinocytes and only observed in laminitic front limbs (10/12 laminitic samples, compared to 0/7 in sections from the hind limbs and 0/5 of controls). Conclusions: These data demonstrate that the endoplasmic reticulum stress pathway is active in naturally occurring cases of laminitis and is most active within a subset of epidermal keratinocytes. These data provide the rationale for further study of endoplasmic reticulum stress in experimental models of laminitis and the links between laminitis and human diseases sharing activation of this stress pathway. Pharmacological options to manipulate the endoplasmic reticulum stress pathway under investigation for human disease could be applicable to laminitis treatment and prevention should this pathway prove to be a driver of disease progression.
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Publication Date: 2019-01-10 PubMed ID: 30630474PubMed Central: PMC6327420DOI: 10.1186/s12917-018-1748-xGoogle Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This study examines the presence of endoplasmic reticulum stress in a disease called laminitis in horses, often associated with hormonal imbalances. The researchers discovered this stress pathway to be active in the affected tissues, providing insights that may guide future treatment strategies.

Background

  • In the study, the researchers were investigating the disease known as laminitis that often affects horses. This disease is commonly associated with endocrinopathies, which are disruptions or disorders of the endocrine system that can lead to an overproduction of insulin (hyperinsulinemia).
  • Chronic over-stimulation of these insulin and growth-related pathways, typical in hyperinsulinemia, can result in a condition known as endoplasmic reticulum stress in the lamellar tissues of the horse.
  • Endoplasmic reticulum stress is linked to tissue pathology and is seen in numerous human metabolic diseases.

Hypothesis and Methodology

  • The researchers hypothesized that endoplasmic reticulum stress might play a significant role in laminitis. To test this hypothesis, they measured the expression levels of protein markers related to endoplasmic reticulum stress in horses affected by endocrinopathic laminitis.
  • A total of 12 horses were examined, and three protein markers — spliced XBP1, Grp78/BiP, and Grp94 — were detected in significantly higher quantities in the lamellar tissues from the front limbs of horses with laminitis.
  • The researchers also compared the front limbs, which were more severely affected, with less affected hind limbs in the same horses.

Results

  • The study found that the protein markers related to endoplasmic reticulum stress were upregulated 2.5-9.5 times more in affected horses compared to control subjects.
  • In a more detailed examination, the protein Grp78/BiP was highly elevated in particular cell types (suprabasal epidermal keratinocytes), indicative of increased endoplasmic reticulum stress.
  • This increased expression was predominantly observed in the front limbs of those horses suffering from laminitis.

Conclusions and Implications

  • These findings demonstrate that endoplasmic reticulum stress pathways are notably active in horses suffering from naturally occurring laminitis, particularly within a subset of epidermal keratinocytes.
  • This discovery provides a reason for further investigation of endoplasmic reticulum stress in experimental models of laminitis and its potential links to human diseases that also activate this stress pathway.
  • The results could have important implications for treating and preventing laminitis if endoplasmic reticulum stress is proven to be a significant factor in the progression of the disease. Potential treatment options for human diseases focused on manipulating the endoplasmic reticulum stress pathway might be applicable here.

Cite This Article

APA
Cassimeris L, Engiles JB, Galantino-Homer H. (2019). Detection of endoplasmic reticulum stress and the unfolded protein response in naturally-occurring endocrinopathic equine laminitis. BMC Vet Res, 15(1), 24. https://doi.org/10.1186/s12917-018-1748-x

Publication

BMC veterinary research
ISSN: 1746-6148
NlmUniqueID: 101249759
Country: England
Language: English
Volume: 15
Issue: 1
Pages: 24
PII: 24

Researcher Affiliations

Cassimeris, Lynne
  • Department of Biological Sciences, Lehigh University, Bethlehem, PA, 18015, USA. lc07@lehigh.edu.
Engiles, Julie B
  • Department of Clinical Studies/New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, 19348, USA.
  • Department of Pathobiology/New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Galantino-Homer, Hannah
  • Department of Clinical Studies/New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, 19348, USA.

MeSH Terms

  • Animals
  • Biomarkers / metabolism
  • Cohort Studies
  • Endoplasmic Reticulum Chaperone BiP
  • Endoplasmic Reticulum Stress
  • Female
  • Foot Diseases / metabolism
  • Foot Diseases / veterinary
  • Hoof and Claw
  • Horse Diseases / metabolism
  • Horses
  • Male
  • Unfolded Protein Response

Conflict of Interest Statement

ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Samples available in the Laminitis Discovery Database repository were collected from horses at the time of euthanasia according to procedures approved by the University of Pennsylvania IACUC. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER’S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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