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Dual deletion of guanylyl cyclase-A and p38 mitogen-activated protein kinase in podocytes with aldosterone administration causes glomerular intra-capillary thrombi.
- Source :
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Kidney international [Kidney Int] 2023 Sep; Vol. 104 (3), pp. 508-525. Date of Electronic Publication: 2023 Jun 24. - Publication Year :
- 2023
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Abstract
- Natriuretic peptides exert not only blood-lowering but also kidney-protective effects through guanylyl cyclase-A (GC-A), a natriuretic peptide receptor. Signaling through GC-A has been shown to protect podocytes from aldosterone-induced glomerular injury, and a p38 mitogen-activated protein kinase (MAPK) inhibitor reduced glomerular injury in aldosterone-infused podocyte-specific GC-A knockout mice. To explore the role of p38 MAPK in podocytes, we constructed podocyte-specific p38 MAPK and GC-A double knockout mice (pod-double knockout mice). Unexpectedly, aldosterone-infused and high salt-fed (B-ALDO)-treated pod-double knockout mice resulted in elevated serum creatinine, massive albuminuria, macrophage infiltration, foot process effacement, nephrin and podocin reduction, and additionally, intra-capillary fibrin thrombi, indicating endothelial injury. Microarray analysis showed increased plasminogen activator inhibitor-1 (PAI-1) in glomeruli of B-ALDO-treated pod-double knockout mice. In B-ALDO-treated pod-double knockout mice, PAI-1 increased in podocytes, and treatment with PAI-1 neutralizing antibody ameliorated intra-capillary thrombus formation. In vitro, deletion of p38 MAPK by the CRISPR/Cas9 system and knockdown of GC-A in human cultured podocytes upregulated PAI-1 and transforming growth factor- β1 (TGF-β1). When p38 MAPK knockout podocytes, transfected with a small interfering RNA to suppress GC-A, were co-cultured with glomerular endothelial cells in a transwell system, the expression of TGF-β1 was increased in glomerular endothelial cells. PAI-1 inhibition ameliorated both podocyte and endothelial injury in the transwell system signifying elevated PAI-1 in podocytes is a factor disrupting normal podocyte-endothelial crosstalk. Thus, our results indicate that genetic dual deletion of p38 MAPK and GC-A in podocytes accelerates both podocyte and endothelial injuries, suggesting these two molecules play indispensable roles in podocyte function.<br /> (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Humans
Mice
Aldosterone pharmacology
Aldosterone metabolism
Endothelial Cells metabolism
Guanylate Cyclase metabolism
Guanylate Cyclase pharmacology
Mice, Knockout
p38 Mitogen-Activated Protein Kinases metabolism
Plasminogen Activator Inhibitor 1 metabolism
Plasminogen Activator Inhibitor 1 pharmacology
Transforming Growth Factor beta1 metabolism
Mitogen-Activated Protein Kinase 14
Podocytes metabolism
Thrombosis metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1523-1755
- Volume :
- 104
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Kidney international
- Publication Type :
- Academic Journal
- Accession number :
- 37356621
- Full Text :
- https://doi.org/10.1016/j.kint.2023.06.007