Inactivation of AMPK Mediates High Phosphate-Induced Extracellular Matrix Accumulation via NOX4/TGFß-1 Signaling in Human Mesangial Cells
| Autor: | Kamila C. Silva, Jacqueline M. Lopes de Faria, José B. Lopes de Faria, Elisa B.M.I. Peixoto, Alexandros Papadimitriou |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Collagen Type IV
AMPK medicine.medical_specialty Physiology Extracellular matrix accumulation Phosphate AMP-Activated Protein Kinases lcsh:Physiology Phosphates Transforming Growth Factor beta1 NOX4 lcsh:Biochemistry chemistry.chemical_compound AMP-activated protein kinase Mesangial cells Superoxides Internal medicine medicine Humans lcsh:QD415-436 Smad3 Protein Phosphorylation Cells Cultured chemistry.chemical_classification Reactive oxygen species NADPH oxidase biology lcsh:QP1-981 Chemistry Superoxide Transforming growth factor ß-1 NADPH Oxidases Actins Extracellular Matrix Fibronectins Cell biology Fibronectin Endocrinology NADPH Oxidase 4 biology.protein Signal transduction Reactive Oxygen Species Signal Transduction |
| Zdroj: | Cellular Physiology and Biochemistry, Vol 34, Iss 4, Pp 1260-1272 (2014) |
| ISSN: | 1421-9778 1015-8987 |
| Popis: | Background/Aims: High phosphate (Pi) levels and extracellular matrix (ECM) accumulation are associated with chronic kidney disease progression. However, how high Pi levels contribute to ECM accumulation in mesangial cells is unknown. The present study investigated the role and mechanism of high Pi levels in ECM accumulation in immortalized human mesangial cells (iHMCs). Methods: iHMCs were exposed to normal (0.9 mM) or increasing Pi concentrations (2.5 and 5 mM) with or without diferent blockers or activators. NOX4, phosphorylated AMPK (p-AMPK), phosphorylated SMAD3 (p-SMAD3), fibronectin (F/N), collagen IV (C-IV) and alpha-smooth muscle actin (α-SMA) expression was assessed via western blot and immunofluorescence. Lucigenin-enhanced chemiluminescence, and dihydroethidium (DHE) assessed NADPH oxidase activity and superoxide (SO), respectively. Results: In iHMCs, a Pi transporter blocker (PFA) abrogated high Pi-induced AMPK inactivation, increase in NADPH oxidase-induced reactive oxygen species (ROS) levels, NOX4, p-SMAD3, α-SMA and C-IV expression. AMPK activation by AICAR, NOX4 silencing or NADPH oxidase blocker prevented high Pi-induced DHE levels, p-SMAD3, F/N, C-IV and α-SMA expression. Conclusion: AMPK inactivation with NOX4-induced ROS formation and transforming growth factor s-1 (TGFs-1) signaling activation mediates high Pi-induced ECM accumulation in iHMCs. Maneuvers increasing AMPK or reducing NOX4 activity may contribute to renal protection under hyperphosphatemia. |
| Databáze: | OpenAIRE |
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