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Extracellular ATP modulates podocyte function through P2Y purinergic receptors and pleiotropic effects on AMPK and cAMP/PKA signaling pathways.
- Source :
-
Archives of biochemistry and biophysics [Arch Biochem Biophys] 2020 Nov 30; Vol. 695, pp. 108649. Date of Electronic Publication: 2020 Oct 22. - Publication Year :
- 2020
-
Abstract
- Podocytes and their foot processes interlinked by slit diaphragms, constitute a continuous outermost layer of the glomerular capillary and seem to be crucial for maintaining the integrity of the glomerular filtration barrier. Purinergic signaling is involved in a wide range of physiological processes in the renal system, including regulating glomerular filtration. We evaluated the role of nucleotide receptors in cultured rat podocytes using non-selective P2 receptor agonists and agonists specific for the P2Y <subscript>1</subscript> , P2Y <subscript>2</subscript> , and P2Y <subscript>4</subscript> receptors. The results showed that extracellular ATP evokes cAMP-dependent pathways through P2 receptors and influences remodeling of the podocyte cytoskeleton and podocyte permeability to albumin via coupling with RhoA signaling. Our findings highlight the relevance of the P2Y <subscript>4</subscript> receptor in protein kinase A-mediated signal transduction to the actin cytoskeleton. We observed increased cAMP concentration and decreased RhoA activity after treatment with a P2Y <subscript>4</subscript> agonist. Moreover, protein kinase A inhibitors reversed P2Y <subscript>4</subscript> -induced changes in RhoA activity and intracellular F-actin staining. P2Y <subscript>4</subscript> stimulation resulted in enhanced AMPK phosphorylation and reduced reactive oxygen species generation. Our findings identify P2Y-PKA-RhoA signaling as the regulatory mechanism of the podocyte contractile apparatus and glomerular filtration. We describe a protection mechanism for the glomerular barrier linked to reduced oxidative stress and reestablished energy balance.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Female
Podocytes cytology
Rats
Rats, Wistar
rho GTP-Binding Proteins metabolism
AMP-Activated Protein Kinases metabolism
Adenosine Triphosphate pharmacokinetics
Cyclic AMP metabolism
Cyclic AMP-Dependent Protein Kinases metabolism
Podocytes metabolism
Receptors, Purinergic P2 metabolism
Second Messenger Systems drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0384
- Volume :
- 695
- Database :
- MEDLINE
- Journal :
- Archives of biochemistry and biophysics
- Publication Type :
- Academic Journal
- Accession number :
- 33122160
- Full Text :
- https://doi.org/10.1016/j.abb.2020.108649