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Matrix metalloproteinase-10 plays an active role in microvascular complications in type 1 diabetic patients

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Abstract

Aims/hypothesis

The role of metalloproteinase-10 (MMP-10) in type 1 diabetes is not known. We hypothesise that it plays a role in the onset and progression of diabetic nephropathy and retinopathy.

Methods

Serum MMP-10 levels from 269 patients with type 1 diabetes were measured, and their association with microvascular complications was analysed. We also studied whether knocking out the Mmp10 gene influenced the extent of renal injury and retinal damage in a streptozotocin-induced diabetic mouse model.

Results

The risk of nephropathy and proliferative retinopathy associated with the highest vs the lowest MMP-10 tertile was increased three to four times independently of the classical risk factors. Accordingly, renal function and morphology were better preserved in diabetic Mmp10 −⁄− mice than in their Mmp10 +/+ counterparts. There were more kidney-infiltrating macrophages in diabetic Mmp10+/+ mice, suggesting that MMP-10 contributes to the inflammatory response leading to microvascular complications. The loss of neuronal cells in the retinas of diabetic Mmp10 +/+ mice was higher than in Mmp10 −⁄− mice. Retinal inflammation was decreased in Mmp10 −⁄− mice, as indicated by their reduced retinal caspase-1 levels.

Conclusions/interpretation

MMP-10 is involved in the development of microvascular complications in type 1 diabetes and emerges as a potential therapeutic target for slowing down the evolution of diabetic nephropathy and retinopathy.

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Abbreviations

INL:

Inner nuclear layer

MMP:

Metalloproteinase

PAS:

Periodic acid–Schiff reagent

STZ:

Streptozotocin

TBS-T:

TRIS-buffered saline/0.05% Tween 20

TR:

Total retinal

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Acknowledgements

We acknowledge Maider Esparza (Laboratory of Thrombosis and Haemostasis, Division of Cardiovascular Sciences, CIMA, University of Navarra, Pamplona, Spain) for her excellent technical assistance. We also thank Josune Orbe and José A. Rodríguez (Laboratory of Atherothrombosis, Division of Cardiovascular Sciences, CIMA, University of Navarra, Pamplona, Spain) for their expert advice on proMMP-10 determination and animal experimentation. We acknowledge all the physicians and nurses from the Endocrinology Service at Navarra Hospital involved in recruitment of patients and sample extraction, and Óscar Beloqui from the Internal Medicine Department of the hospital of the University of Navarra.

Funding

This work was supported through the Unión Temporal de Empresas project CIMA and by grants from the Health Department of the Navarra Government, Spain (project 12075301) and Instituto de Salud Carlos III (Red Temática de Investigación RECAVA RD06/0014/0008). ET is supported by a Rio Hortega post-residency fellowship from the Instituto de Salud Carlos III, Ministry of Economy and Competitiveness, Spanish Government.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

MT participated in the design of the whole project, researched data, performed the histological study and wrote, reviewed and edited the manuscript; JH participated in the design of the whole project, supervised the work and the creation of the article and reviewed the manuscript; MJG participated in the design of the project, recruited the patients and reviewed the manuscript; PF participated in the design of the project, was in charge of the histological studies of the retinas and reviewed the manuscript; WCP participated in the design of the project, provided the Mmp10 −/− mice and reviewed the manuscript; ET participated in the design of the project, was in charge of the statistical analyses and reviewed the manuscript; RM participated in the design of the project, reviewed the whole article and made important contributions to the final edition of the manuscript; ND was in charge of the whole project design and supervised the performance of the work and the creation of the article. All authors have read the manuscript and approved the final version to be published. This manuscript has not been published and is not being considered for publication elsewhere, in whole or in part, in any language. ND is the guarantor of the work and had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Authors and Affiliations

  1. Department of Endocrinology, Navarra Hospital, Pamplona, Spain

    Marta Toni & María J. Goñi

  2. Division of Cardiovascular Sciences, Laboratory of Thrombosis and Haemostasis, Centre for Applied Medical Research, University of Navarra, Avenida Pío XII, 55, 31008, Pamplona, Spain

    José Hermida, Ramón Montes & Nieves Díez

  3. Department of Ophthalmology, University of Navarra, Pamplona, Spain

    Patricia Fernández

  4. Center for Lung Biology, University of Washington School of Medicine, Seattle, WA, USA

    William C. Parks

  5. Department of Preventive Medicine and Public Health, School of Medicine, University of Navarra, Pamplona, Spain

    Estefanía Toledo

  6. CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain

    Estefanía Toledo

  7. Department of Human Physiology, School of Medicine, University of Navarra, Pamplona, Spain

    Nieves Díez

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  1. Marta Toni
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Correspondence to Nieves Díez.

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Toni, M., Hermida, J., Goñi, M.J. et al. Matrix metalloproteinase-10 plays an active role in microvascular complications in type 1 diabetic patients. Diabetologia 56, 2743–2752 (2013). https://doi.org/10.1007/s00125-013-3052-4

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  • DOI: https://doi.org/10.1007/s00125-013-3052-4

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