Mesangioproliferative Kidney Diseases and Platelet-Derived Growth Factor-Mediated AXL Phosphorylation.
Kidney Med
; 3(6): 1003-1013.e1, 2021.
Article
in En
| MEDLINE
| ID: mdl-34939009
ABSTRACT
RATIONALE & OBJECTIVE:
Immunoglobulin A nephropathy (IgAN) is a common glomerular disease, with mesangial cell proliferation as a major feature. There is no disease-specific treatment. Platelet-derived growth factor (PDGF) contributes to the pathogenesis of IgAN. To better understand its pathogenic mechanisms, we assessed PDGF-mediated AXL phosphorylation in human mesangial cells and kidney tissue biopsy specimens. STUDYDESIGN:
Immunostaining using human kidney biopsy specimens and in vitro studies using primary human mesangial cells. SETTING &PARTICIPANTS:
Phosphorylation of AXL was assessed in cultured mesangial cells and 10 kidney-biopsy specimens from 5 patients with IgAN, 3 with minimal change disease, 1 with membranous nephropathy, and 1 with mesangioproliferative glomerulonephritis (GN). PREDICTOR Glomerular staining for phospho-AXL in kidney biopsy specimens of patients with mesangioproliferative diseases.OUTCOMES:
Phosphorylated AXL detected in biopsy tissues of patients with IgAN and mesangioproliferative GN and in cultured mesangial cells stimulated with PDGF. ANALYTICAPPROACH:
t test, Mann-Whitney test, and analysis of variance were used to assess the significance of mesangial cell proliferative changes.RESULTS:
Immunohistochemical staining revealed enhanced phosphorylation of glomerular AXL in IgAN and mesangioproliferative GN, but not in minimal change disease and membranous nephropathy. Confocal-microscopy immunofluorescence analysis indicated that mesangial cells rather than endothelial cells or podocytes expressed phospho-AXL. Kinomic profiling of primary mesangial cells treated with PDGF revealed activation of several protein-tyrosine kinases, including AXL. Immunoprecipitation experiments indicated association of AXL and PDGF receptor proteins. An AXL-specific inhibitor (bemcentinib) partially blocked PDGF-induced cellular proliferation and reduced phosphorylation of AXL and PDGF receptor and the downstream signals (AKT1 and ERK1/2).LIMITATIONS:
Small number of kidney biopsy specimens to correlate the activation of AXL with disease severity.CONCLUSIONS:
PDGF-mediated signaling in mesangial cells involves transactivation of AXL. Finding appropriate inhibitors to block PDGF-mediated transactivation of AXL may provide new therapeutic options for mesangioproliferative kidney diseases such as IgAN.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Type of study:
Prognostic_studies
Language:
En
Journal:
Kidney Med
Year:
2021
Document type:
Article
Affiliation country:
Albania