Danegaptide Prevents TGFβ1-Induced Damage in Human Proximal Tubule Epithelial Cells of the Kidney
| Autor: | Claire E. Hills, Gareth Price, Bethany M Williams, Paul E. Squires, Ulrik Mouritzen, Joe A. Potter |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
connexin
hemichannel medicine.medical_treatment danegaptide Inflammation Article Catalysis Cell Line Proinflammatory cytokine Kidney Tubules Proximal Transforming Growth Factor beta1 lcsh:Chemistry Inorganic Chemistry Adherens junction medicine Humans Secretion Renal Insufficiency Chronic Physical and Theoretical Chemistry lcsh:QH301-705.5 Molecular Biology Spectroscopy Tight junction Chemistry fibrosis TGFβ1 Organic Chemistry C130 Cell Biology B131 Cellular Pathology Epithelial Cells Dipeptides General Medicine hPTECs Computer Science Applications Cell biology ATP Cytokine lcsh:Biology (General) lcsh:QD1-999 inflammation Paracellular transport A100 Pre-clinical Medicine medicine.symptom chronic kidney disease Transforming growth factor |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 2809, p 2809 (2021) International Journal of Molecular Sciences Volume 22 Issue 6 |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms22062809 |
| Popis: | Chronic kidney disease (CKD) is a global health problem associated with a number of comorbidities. Recent evidence implicates increased hemichannel-mediated release of adenosine triphosphate (ATP) in the progression of tubulointerstitial fibrosis, the main underlying pathology of CKD. Here, we evaluate the effect of danegaptide on blocking hemichannel-mediated changes in the expression and function of proteins associated with disease progression in tubular epithelial kidney cells. Primary human proximal tubule epithelial cells (hPTECs) were treated with the beta1 isoform of the pro-fibrotic cytokine transforming growth factor (TGFβ1) ± danegaptide. qRT-PCR and immunoblotting confirmed mRNA and protein expression, whilst a cytokine antibody array assessed the expression/secretion of proinflammatory and profibrotic cytokines. Carboxyfluorescein dye uptake and ATP biosensing measured hemichannel activity and ATP release, whilst transepithelial electrical resistance was used to assess paracellular permeability. Danegaptide negated carboxyfluorescein dye uptake and ATP release and protected against protein changes associated with tubular injury. Blocking Cx43-mediated ATP release was paralleled by partial restoration of the expression of cell cycle inhibitors, adherens and tight junction proteins and decreased paracellular permeability. Furthermore, danegaptide inhibited TGFβ1-induced changes in the expression and secretion of key adipokines, cytokines, chemokines, growth factors and interleukins. The data suggest that as a gap junction modulator and hemichannel blocker, danegaptide has potential in the future treatment of CKD. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|