In vivo studies demonstrate that endothelin-1 traps are a potential therapy for type I diabetes

Abstract

Background

Type 1 diabetes is a serious, lifelong condition where the body’s blood glucose level increases because of the body’s inability to make insulin. An important consequence of this is the increased expression of extracellular matrix proteins, such as fibronectin and collagen 4α1, in key tissues and organs like the heart and kidneys. Diabetes is also associated with increased plasma levels of the vasoactive peptide endothelin (ET)-1. This further aggravates the expression of the ECM proteins. There are also important consequences of increased glucose and ET-1 levels in diabetes on the heart, termed diabetic cardiomyopathy.

Methods

We have previously reported the development of ET-traps, which potently and significantly reduce pathological levels of ET-1. In this study, we tested the in vivo therapeutic potential of ET-traps for type 1 diabetes using the B6 mouse model.

Results

Following subcutaneous administration of ET-traps 3 times a week, over a 2 month period, the 500 nM dose of ET-traps gave a significant reduction in collagen 4α1 expression in the heart and kidney, returning it back to control, non-diabetic levels at both the mRNA and protein levels. The expression of fibronectin mRNA is also returned to control levels with the 500 nM dose of ET-traps. The efficacy of ET-traps for type 1 diabetes was further evinced by immunohistochemistry data, echocardiography studies (measuring left ventricular systolic function and diastolic dysfunction) and a measure of urine creatinine and albumin levels. In all analyses, the 500 nM dose of ET-traps returns the different measures to control, non-diabetic levels.

Conclusion

Data from this study show that in a mouse model ET-traps have a potent and significant therapeutic effect on diabetes disease pathology. Future studies could further evaluate the use of ET-traps as a therapy for diabetes, including taking them through clinical trials.

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Abbreviations

ALT:

Alanine aminotransferase

AST:

Aspartate transaminase

CKD:

Chronic kidney disease

DTI:

Doppler tissue imaging

ET-1:

Endothelin-1

ECM:

Extracellular matrix

ESRD:

End-stage renal disease

ETtr:

Endothelin-1 traps

FN:

Fibronectin

STZ:

Streptozotocin

T1D:

Type 1 diabetes

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Funding

This project was privately funded.

Author information

Affiliations

Authors

Contributions

AJ participated in the research design. The in vivo testing experiments were contracted out as stated at the beginning of the Materials and methods. AJ, AJ and VM contributed new reagents or analytic tools. AJ, VM, IJ and AJ wrote or contributed to the writing of the manuscript.

Corresponding author

Correspondence to Arjun Jain.

Ethics declarations

Ethics approval statement

All experiments conformed to the Guide For the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH publication no. 85–23, revised in 1996). Experimental protocols were reviewed and approved by the Western University council on animal care committee.

Conflict of interest

AJ, VM and AJ are members of Accelerate Cambridge, University of Cambridge, UK.

Declaration statement

Any inquiries on data of this study can be directed to Dr. Arjun Jain.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Key points

ET-traps have a very high binding affinity.

ET-traps significantly return different markers of pathology to basal levels (have a therapeutic effect) in an in vivo model of diabetes.

ET-traps are non-toxic.

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Jain, A., Mehrotra, V., Jha, I. et al. In vivo studies demonstrate that endothelin-1 traps are a potential therapy for type I diabetes. J Diabetes Metab Disord 18, 133–143 (2019). https://doi.org/10.1007/s40200-019-00400-7

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Keywords

  • DM, Diabetes mellitus
  • ECM, Extracellular matrix
  • ET-1, Endothelin-1
  • ETtr, Endothelin-1 traps
  • FFP, Fc-fusion protein