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



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.


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.


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.


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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Alanine aminotransferase


Aspartate transaminase


Chronic kidney disease


Doppler tissue imaging




Extracellular matrix


End-stage renal disease


Endothelin-1 traps






Type 1 diabetes


  1. 1.

    Noble JA, Erlich HA. Genetics of type 1 diabetes. Cold Spring Harb Perspect Med. 2012;2(1):a007732.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Steck AK, Rewers MJ. Genetics of type 1 diabetes. Clin Chem. 2011;57(2):176–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Escher S, Sandholzer H. The epidemiology of type 1 diabetes mellitus. 2013;1–22.

  4. 4.

    Maahs DM, et al. Epidemiology of type 1 diabetes. Endocrinol Metab Clin N Am. 2010;39(3):481–97.

    Article  Google Scholar 

  5. 5.

    Fernandes JR, et al. IDF Diabetes Atlas estimates of 2014 global health expenditures on diabetes. Diabetes Res Clin Pract. 2016;117(2016):48–54.

  6. 6.

    Melmed S, et. al. Williams textbook of endocrinology, 2011.

  7. 7.

    Law B, et al. Diabetes-induced alterations in the extracellular matrix and their impact on myocardial function. Microsc Microanal. 2012;18(1):22–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Evans T, et al. Endothelin receptor blockade prevents augmented extracellular matrix component mRNA expression and capillary basement membrane thickening in the retina of diabetic and galactose-fed rats. Diabetes. 2000;49(4):662–6.

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Chen S, et al. High glucose-induced, endothelin-dependent fibronectin synthesis is mediated via NF-kappa B and AP-1. Am J Physiol Cell Physiol. 2003;284(2):C263–72.

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Jain A, et al. Endothelin-1 traps potently reduce pathologic markers back to basal levels in an in vitro model of diabetes. J Diabetes Metab Disord. 2018.

  11. 11.

    Simonson MS, Ismail-Beigi F. Endothelin-1 increases collagen accumulation in renal mesangial cells by stimulating a chemokine and cytokine autocrine signaling loop. J Biol Chem. 2011;286(13):11003–8.

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Seligman BG, et al. Increased plasma levels of endothelin 1 and von Willebrand factor in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2000;23(9):1395–400.

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Schneider JG, et al. Elevated plasma endothelin-1 levels in diabetes mellitus. Am J Hypertens. 2002;15(11):967–72.

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Stehouwer CD, et al. Endothelial dysfunction and pathogenesis of diabetic angiopathy. Cardiovasc Res. 1997;34(1):55–68.

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    De Caterina R. Endothelial dysfunctions: common denominators in vascular disease. Curr Opin Clin Nutr Metab Care. 2000;3(6):453–67.

    Article  PubMed  Google Scholar 

  16. 16.

    Deanfield J, et al. Endothelial function and dysfunction. Part I: methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension. J Hypertens. 2005;23(1):7–17.

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Bohm F, Pernow J. The importance of endothelin-1 for vascular dysfunction in cardiovascular disease. Cardiovasc Res. 2007;76(1):8–18.

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    He, Z. Role of PKC[delta] and Endothelin-1 in Diabetic Cardiomyopathy. In 66th Scientific Sessions 2006. American Diabetes Association.

  19. 19.

    Jun R, Chiming W. New sniper assignment for a celebrity-role of endothelin-1 in diabetic cardiomyopathy. Journal of Cardiothoracic - Renal Research. 2006;1(1):30–2.

    Article  Google Scholar 

  20. 20.

    Seymour, T., What is diabetic nephropathy?, in Medical News Today. 2017.

  21. 21.

    A Shahriar, et al. Diabetic nephropathy, Pathophysiology and complications of diabetes mellitus; 2012.

  22. 22.

    Dabla PK. Renal function in diabetic nephropathy. World J Diabetes. 2010;1(2):48–56.

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Georgianos PI, Agarwal R. Endothelin a receptor antagonists in diabetic kidney disease. Curr Opin Nephrol Hypertens. 2017;26(5):338–44.

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Chen S, et al. miR-146a regulates glucose induced upregulation of inflammatory cytokines extracellular matrix proteins in the retina and kidney in diabetes. PLoS One. 2017;12(3):e0173918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Thomas AA, Feng B, Chakrabarti S. ANRIL regulates production of extracellular matrix proteins and vasoactive factors in diabetic complications. Am J Physiol Endocrinol Metab. 2018;314(3):E191–200.

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Feng B, et al. miR-146a mediates inflammatory changes and fibrosis in the heart in diabetes. J Mol Cell Cardiol. 2017;105:70–6.

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Chen S, et al. Differential activation of NF-kappa B and AP-1 in increased fibronectin synthesis in target organs of diabetic complications. Am J Physiol Endocrinol Metab. 2003;284(6):E1089–97.

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Wu Y, et al. ERK5 contributes to VEGF alteration in diabetic retinopathy. J Ophthalmol. 2010;2010:465824.

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Roy S, et al. Overexpression of fibronectin induced by diabetes or high glucose: phenomenon with a memory; 1990;87(1):404–8.

  30. 30.

    Morrish NJ, et al. Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia. 2001;44(Suppl 2):S14–21.

    Article  PubMed  Google Scholar 

  31. 31.

    Lip G, Hall J. Comprehensive hypertension. ScienceDirect. 2007.

  32. 32.

    Mishra PK, et al. Diabetic cardiomyopathy: an Immunometabolic perspective. Front Endocrinol (Lausanne). 2017;8:72.

    Article  Google Scholar 

  33. 33.

    Cosson S, Kevorkian JP. Left ventricular diastolic dysfunction: an early sign of diabetic cardiomyopathy? Diabetes Metab. 2003;29(5):455–66.

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Slavica M, Biljana L. Contemporary echocardiographic techniques in early detection of diabetic cardiomyopathy. Journal of Cardiology and Current Research. 2014.

  35. 35.

    Townsend JC. Increased albumin excretion in diabetes. J Clin Pathol. 1990;43(1):3–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Kos I, Prkačin I. Diabetic nephropathy as a cause of chronic kidney disease. Acta Med Croatica. 2014;68(4–5):375–81.

    PubMed  Google Scholar 

  37. 37.

    Genovese F, et al. The extracellular matrix in the kidney: a source of novel non-invasive biomarkers of kidney fibrosis? Fibrogenesis Tissue Repair. 2014;7(1):4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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This project was privately funded.

Author information




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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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).

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