Adenosine A<sub>2B</sub> Receptor Antagonism Interferes with TGF-β Cellular Signaling Through SMAD2/-3 and p65-Nf-κB in Podocytes and Protects from Phenotypical Transformation in Experimental Diabetic Glomerulopathy
Studies have emphasized alleviating fibrogenesis through interference with adenosine signaling in experimental diabetic nephropathy. We found that the in vivo antagonism of the adenosine A<sub>2B</sub> receptor (A<sub>2B</sub>AR) using MRS1754 in diabetic rats impedes the dia...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-06-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/14/12/890 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849432432675127296 |
|---|---|
| author | Ignacio Arias Claudia Jara Pablo Mendoza-Soto Yessica Nahuelpán Claudio Cappelli Carlos Oyarzún Diego Carrillo-Beltrán Claudia Quezada-Monrás Angelo Torres-Arévalo Rody San Martín |
| author_facet | Ignacio Arias Claudia Jara Pablo Mendoza-Soto Yessica Nahuelpán Claudio Cappelli Carlos Oyarzún Diego Carrillo-Beltrán Claudia Quezada-Monrás Angelo Torres-Arévalo Rody San Martín |
| author_sort | Ignacio Arias |
| collection | DOAJ |
| description | Studies have emphasized alleviating fibrogenesis through interference with adenosine signaling in experimental diabetic nephropathy. We found that the in vivo antagonism of the adenosine A<sub>2B</sub> receptor (A<sub>2B</sub>AR) using MRS1754 in diabetic rats impedes the diabetes-induced glomerular expression of the mesenchymal-like transformation markers Snail and α-SMA, while the loss of the epithelial podocyte-specific proteins nephrin and ZO-1 was prevented. Furthermore, the production of MCP-1, CCL3, TGF-β, and the transcript levels of inflammatory mediators was reduced by A<sub>2B</sub>AR antagonism. Using human podocytes in vitro, we demonstrated that A<sub>2B</sub>AR antagonism affected the TGF-β-induced activation of SMAD2/-3, as evidenced by the attenuated phosphorylation of SMAD2/-3 and decreased SMAD3 occupancy at target gene promoters following the MRS1754 treatment. Moreover, the non-canonical activation of p65-NF-κB, the primary inflammatory signaling pathway downstream of TGF-β, and the expression of Snail were also reduced by MRS1754. We conclude that an A<sub>2B</sub>AR blockade interferes with the pathogenic TGF-β signaling cascade responsible for the phenotypical transformation of podocytes, thereby alleviating diabetic glomerulopathy. |
| format | Article |
| id | doaj-art-5621bf71f66c4b97956c52e10dc5892a |
| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj-art-5621bf71f66c4b97956c52e10dc5892a2025-08-20T03:27:22ZengMDPI AGCells2073-44092025-06-01141289010.3390/cells14120890Adenosine A<sub>2B</sub> Receptor Antagonism Interferes with TGF-β Cellular Signaling Through SMAD2/-3 and p65-Nf-κB in Podocytes and Protects from Phenotypical Transformation in Experimental Diabetic GlomerulopathyIgnacio Arias0Claudia Jara1Pablo Mendoza-Soto2Yessica Nahuelpán3Claudio Cappelli4Carlos Oyarzún5Diego Carrillo-Beltrán6Claudia Quezada-Monrás7Angelo Torres-Arévalo8Rody San Martín9Molecular Pathology Laboratory, Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia 5110566, ChileMolecular Pathology Laboratory, Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia 5110566, ChileMolecular Pathology Laboratory, Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia 5110566, ChileMolecular Pathology Laboratory, Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia 5110566, ChileMolecular Pathology Laboratory, Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia 5110566, ChileMolecular Pathology Laboratory, Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia 5110566, ChileTumor Biology Laboratory, Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia 5110566, ChileTumor Biology Laboratory, Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia 5110566, ChileEscuela de Medicina Veterinaria, Facultad de Medicina Veterinaria y Recursos Naturales, Sede Talca, Universidad Santo Tomás, Talca 3473620, ChileMolecular Pathology Laboratory, Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia 5110566, ChileStudies have emphasized alleviating fibrogenesis through interference with adenosine signaling in experimental diabetic nephropathy. We found that the in vivo antagonism of the adenosine A<sub>2B</sub> receptor (A<sub>2B</sub>AR) using MRS1754 in diabetic rats impedes the diabetes-induced glomerular expression of the mesenchymal-like transformation markers Snail and α-SMA, while the loss of the epithelial podocyte-specific proteins nephrin and ZO-1 was prevented. Furthermore, the production of MCP-1, CCL3, TGF-β, and the transcript levels of inflammatory mediators was reduced by A<sub>2B</sub>AR antagonism. Using human podocytes in vitro, we demonstrated that A<sub>2B</sub>AR antagonism affected the TGF-β-induced activation of SMAD2/-3, as evidenced by the attenuated phosphorylation of SMAD2/-3 and decreased SMAD3 occupancy at target gene promoters following the MRS1754 treatment. Moreover, the non-canonical activation of p65-NF-κB, the primary inflammatory signaling pathway downstream of TGF-β, and the expression of Snail were also reduced by MRS1754. We conclude that an A<sub>2B</sub>AR blockade interferes with the pathogenic TGF-β signaling cascade responsible for the phenotypical transformation of podocytes, thereby alleviating diabetic glomerulopathy.https://www.mdpi.com/2073-4409/14/12/890diabetic nephropathyTGF-beta 1adenosine receptorsglomerulosclerosis |
| spellingShingle | Ignacio Arias Claudia Jara Pablo Mendoza-Soto Yessica Nahuelpán Claudio Cappelli Carlos Oyarzún Diego Carrillo-Beltrán Claudia Quezada-Monrás Angelo Torres-Arévalo Rody San Martín Adenosine A<sub>2B</sub> Receptor Antagonism Interferes with TGF-β Cellular Signaling Through SMAD2/-3 and p65-Nf-κB in Podocytes and Protects from Phenotypical Transformation in Experimental Diabetic Glomerulopathy Cells diabetic nephropathy TGF-beta 1 adenosine receptors glomerulosclerosis |
| title | Adenosine A<sub>2B</sub> Receptor Antagonism Interferes with TGF-β Cellular Signaling Through SMAD2/-3 and p65-Nf-κB in Podocytes and Protects from Phenotypical Transformation in Experimental Diabetic Glomerulopathy |
| title_full | Adenosine A<sub>2B</sub> Receptor Antagonism Interferes with TGF-β Cellular Signaling Through SMAD2/-3 and p65-Nf-κB in Podocytes and Protects from Phenotypical Transformation in Experimental Diabetic Glomerulopathy |
| title_fullStr | Adenosine A<sub>2B</sub> Receptor Antagonism Interferes with TGF-β Cellular Signaling Through SMAD2/-3 and p65-Nf-κB in Podocytes and Protects from Phenotypical Transformation in Experimental Diabetic Glomerulopathy |
| title_full_unstemmed | Adenosine A<sub>2B</sub> Receptor Antagonism Interferes with TGF-β Cellular Signaling Through SMAD2/-3 and p65-Nf-κB in Podocytes and Protects from Phenotypical Transformation in Experimental Diabetic Glomerulopathy |
| title_short | Adenosine A<sub>2B</sub> Receptor Antagonism Interferes with TGF-β Cellular Signaling Through SMAD2/-3 and p65-Nf-κB in Podocytes and Protects from Phenotypical Transformation in Experimental Diabetic Glomerulopathy |
| title_sort | adenosine a sub 2b sub receptor antagonism interferes with tgf β cellular signaling through smad2 3 and p65 nf κb in podocytes and protects from phenotypical transformation in experimental diabetic glomerulopathy |
| topic | diabetic nephropathy TGF-beta 1 adenosine receptors glomerulosclerosis |
| url | https://www.mdpi.com/2073-4409/14/12/890 |
| work_keys_str_mv | AT ignacioarias adenosineasub2bsubreceptorantagonisminterfereswithtgfbcellularsignalingthroughsmad23andp65nfkbinpodocytesandprotectsfromphenotypicaltransformationinexperimentaldiabeticglomerulopathy AT claudiajara adenosineasub2bsubreceptorantagonisminterfereswithtgfbcellularsignalingthroughsmad23andp65nfkbinpodocytesandprotectsfromphenotypicaltransformationinexperimentaldiabeticglomerulopathy AT pablomendozasoto adenosineasub2bsubreceptorantagonisminterfereswithtgfbcellularsignalingthroughsmad23andp65nfkbinpodocytesandprotectsfromphenotypicaltransformationinexperimentaldiabeticglomerulopathy AT yessicanahuelpan adenosineasub2bsubreceptorantagonisminterfereswithtgfbcellularsignalingthroughsmad23andp65nfkbinpodocytesandprotectsfromphenotypicaltransformationinexperimentaldiabeticglomerulopathy AT claudiocappelli adenosineasub2bsubreceptorantagonisminterfereswithtgfbcellularsignalingthroughsmad23andp65nfkbinpodocytesandprotectsfromphenotypicaltransformationinexperimentaldiabeticglomerulopathy AT carlosoyarzun adenosineasub2bsubreceptorantagonisminterfereswithtgfbcellularsignalingthroughsmad23andp65nfkbinpodocytesandprotectsfromphenotypicaltransformationinexperimentaldiabeticglomerulopathy AT diegocarrillobeltran adenosineasub2bsubreceptorantagonisminterfereswithtgfbcellularsignalingthroughsmad23andp65nfkbinpodocytesandprotectsfromphenotypicaltransformationinexperimentaldiabeticglomerulopathy AT claudiaquezadamonras adenosineasub2bsubreceptorantagonisminterfereswithtgfbcellularsignalingthroughsmad23andp65nfkbinpodocytesandprotectsfromphenotypicaltransformationinexperimentaldiabeticglomerulopathy AT angelotorresarevalo adenosineasub2bsubreceptorantagonisminterfereswithtgfbcellularsignalingthroughsmad23andp65nfkbinpodocytesandprotectsfromphenotypicaltransformationinexperimentaldiabeticglomerulopathy AT rodysanmartin adenosineasub2bsubreceptorantagonisminterfereswithtgfbcellularsignalingthroughsmad23andp65nfkbinpodocytesandprotectsfromphenotypicaltransformationinexperimentaldiabeticglomerulopathy |