کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8949204 | 1666279 | 2018 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Mechanisms underlying modulation of podocyte TRPC6 channels by suPAR: Role of NADPH oxidases and Src family tyrosine kinases
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کلمات کلیدی
PP2NSC23766Gp91phoxTRPC5Cilengitidep47phoxNox2NOX4CGTFSGSTRPC6SRCNADPH oxidase 2 - NADPH اکسیداز 2NADPH oxidase 4 - NADPH اکسیداز 4ROS - ROSapo - آپوApocynin - آپوسیینینIntegrins - اینتگرینchronic kidney disease - بیماری مزمن کلیویTempol - سریعsuPAR - ناراحتCKD - نارسایی مزمن کلیهfocal and segmental glomerulosclerosis - گلومرول اسکلروز مرکزی و سگمنتالReactive oxygen species - گونههای فعال اکسیژنsoluble urokinase receptor - گیرنده یورکیناز محلول
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
سالمندی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
The soluble urokinase receptor (suPAR) has been implicated in the pathogenesis of chronic kidney diseases (CKD) and may function as a circulating “permeability factor” driving primary focal and segmental glomerulosclerosis (FSGS). Here we examined the mechanisms whereby suPAR causes mobilization and increased activation of Ca2+-permeable TRPC6 channels, which are also implicated in FSGS. Treatment of immortalized mouse podocytes with recombinant suPAR for 24â¯h caused a marked increase in cytosolic reactive oxygen species (ROS) that required signaling through integrins. This effect was associated with increased assembly of active cell surface NADPH oxidase 2 (Nox2) complexes and was blocked by the Nox2 inhibitor apoycynin. Treatment with suPAR also evoked a functionally measurable increase in TRPC6 channels that was blocked by concurrent treatment with the ROS-quencher TEMPOL as well as by inhibition of Rac1, an essential component of active Nox2 complexes. Elevated ROS evoked by exposing cells to suPAR or H2O2 caused a marked increase in the abundance of tyrosine-phosphorylated proteins including Src, and suPAR-evoked Src activation was blocked by TEMPOL. Moreover, mobilization and increased activation of TRPC6 by suPAR or H2O2 was blocked by concurrent exposure to PP2, an inhibitor of Src family tyrosine kinases. These data suggest that suPAR induces oxidative stress in podocytes that in turn drives signaling through Src family kinases to upregulate TRPC6 channels. The combination of oxidative stress and altered Ca2+ signaling may contribute to loss of podocytes and progression of various forms of CKD.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease - Volume 1864, Issue 10, October 2018, Pages 3527-3536
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease - Volume 1864, Issue 10, October 2018, Pages 3527-3536
نویسندگان
Eun Young Kim, Naghmeh Hassanzadeh Khayyat, Stuart E. Dryer,