期刊
KIDNEY INTERNATIONAL
卷 100, 期 4, 页码 809-823出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2021.05.036
关键词
glomerular endothelial cell; NF-kappa B; podocyte; Rarres1
资金
- Diabetes Wellness Sverige
- KI/AZ Integrated Metabolic Center
- Marianne och Marcus Wallenberg Foundation
- Swedish Diabetes Foundation
- Swedish Kidney Foundation
- Center for Innovative Medicine
Inflammatory pathways are activated in most glomerular diseases, with the induction of Rarres1 expression being a common molecular mechanism in chronic kidney diseases. The overexpression of Rarres1 in endothelial cells promotes kidney damage in a model of glomerulonephritis through the Nuclear Factor-kappa B signaling pathway, highlighting its pathogenic role in inflammation and fibrosis.
Inflammatory pathways are activated in most glomerular diseases but molecular mechanisms driving them in kidney tissue are poorly known. We identified retinoic acid receptor responder 1 (Rarres1) as a highly podocyteenriched protein in healthy kidneys. Studies in podocytespecific knockout animals indicated that Rarres1 was not needed for the normal development or maintenance of the glomerulus filtration barrier and did not modulate the outcome of kidney disease in a model of glomerulonephritis. Interestingly, we detected an induction of Rarres1 expression in glomerular and peritubular capillary endothelial cells in IgA and diabetic kidney disease, as well as in ANCA-associated vasculitis. Analysis of publicly available RNA data sets showed that the induction of Rarres1 expression was a common molecular mechanism in chronic kidney diseases. A conditional knock-in mouse line, overexpressing Rarres1 specifically in endothelial cells, did not show any obvious kidney phenotype. However, the overexpression promoted the progression of kidney damage in a model of glomerulonephritis. In line with this, conditional knock-out mice, lacking Rarres1 in endothelial cells, were partially protected in the disease model. Mechanistically, Rarres1 promoted inflammation and fibrosis via transcription factor Nuclear Factor-kappa B signaling pathway by activating receptor tyrosine kinase Axl. Thus, induction of Rarres1 expression in endothelial cells is a prevalent molecular mechanism in human glomerulopathies and this seems to have a pathogenic role in driving inflammation and fibrosis via the Nuclear Factor kappa B signaling pathway.
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