Na+/Ca(2+ )Exchanger a Druggable Target to Promote beta -Cell Proliferation and Function
| Autor: | Francesco Paolo Zummo, Julien Papin, André Herchuelz, Romano Regazzi, Alessandra K Cardozo, Claudiane Guay, Nathalie Pachera |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Small interfering RNA Diabetes Pancreatic and Gastrointestinal Hormones Endocrinology Diabetes and Metabolism Cell 030209 endocrinology & metabolism Calcineurein/NFAT pathway 03 medical and health sciences 0302 clinical medicine medicine Research Articles diabetes biology Chemistry Cell growth Diabetes calcineurein/NFAT pathway Retinoblastoma protein NFAT Généralités Na/Ca exchange β-cell Sciences bio-médicales et agricoles Cell cycle Cell biology Calcineurin 030104 developmental biology medicine.anatomical_structure biology.protein Pancreatic islet transplantation |
| Zdroj: | Journal of the Endocrine Society, vol. 2, no. 7, pp. 631-645 Journal of the Endocrine Society, 2 (7 Journal of the Endocrine Society |
| Popis: | An important feature of type 2 diabetes is a decrease in β-cell mass. Therefore, it is essential to find new approaches to stimulate β-cell proliferation. We have previously shown that heterozygous inactivation of the Na+/Ca2+ exchanger (isoform 1; NCX1), a protein responsible for Ca2+ extrusion from cells, increases β-cell proliferation, mass, and function in mice. Here, we show that Ncx1 inactivation also increases β-cell proliferation in 2-year-old mice and that NCX1 inhibition in adult mice by four small molecules of the benzoxyphenyl family stimulates β-cell proliferation both in vitro and in vivo. NCX1 inhibition by small interfering RNA or small molecules activates the calcineurin/nuclear factor of activated T cells (NFAT) pathway and inhibits apoptosis induced by the immunosuppressors cyclosporine A (CsA) and tacrolimus in insulin-producing cell. Moreover, NCX1 inhibition increases the expression of β-cell-specific genes, such as Ins1, Ins2, and Pdx1, and inactivates/downregulates the tumor suppressors retinoblastoma protein (pRb) and miR-193a and the cell cycle inhibitor p53. Our data show that Na+/Ca2+ exchange is a druggable target to stimulate β-cell function and proliferation. Specific β-cell inhibition of Na+/Ca2+ exchange by phenoxybenzamyl derivatives may represent an innovative approach to promote β-cell regeneration in diabetes and improve the efficiency of pancreatic islet transplantation for the treatment of the disease. SCOPUS: ar.j info:eu-repo/semantics/published |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|