Glomerular endothelial cell heterogeneity in Alport syndrome
SCIENTIFIC REPORTS
Authors: Soloyan, Hasmik; Thornton, Matthew; Villani, Valentina; Khatchadourian, Patrick; Cravedi, Paolo; Angeletti, Andrea; Grubbs, Brendan; De Filippo, Roger; Perin, Laura; Sedrakyan, Sargis
Abstract
Glomerular endothelial cells (GEC) are a crucial component of the glomerular physiology and their damage contributes to the progression of chronic kidney diseases. How GEC affect the pathology of Alport syndrome (AS) however, is unclear. We characterized GEC from wild type (WT) and col4 alpha 5 knockout AS mice, a hereditary disorder characterized by progressive renal failure. We used endothelial-specific Tek-tdTomato reporter mice to isolate GEC by FACS and performed transcriptome analysis on them from WT and AS mice, followed by in vitro functional assays and confocal and intravital imaging studies. Biopsies from patients with chronic kidney disease, including AS were compared with our findings in mice. We identified two subpopulations of GEC (dim(tdT) and bright(tdT)) based on the fluorescence intensity of the Tek(tdT) signal. In AS mice, the bright(tdT) cell number increased and presented differential expression of endothelial markers compared to WT. RNA-seq analysis revealed differences in the immune and metabolic signaling pathways. In AS mice, dim(tdT) and bright(tdT) cells had different expression profiles of matrix-associated genes (Svep1, Itg beta 6), metabolic activity (Apom, Pgc1 alpha) and immune modulation (Apelin, Icam1) compared to WT mice. We confirmed a new pro-inflammatory role of Apelin in AS mice and in cultured human GEC. Gene modulations were identified comparable to the biopsies from patients with AS and focal segmental glomerulosclerosis, possibly indicating that the same mechanisms apply to humans. We report the presence of two GEC subpopulations that differ between AS and healthy mice or humans. This finding paves the way to a better understanding of the pathogenic role of GEC in AS progression and could lead to novel therapeutic targets.
Synthesis, O-2-binding ability and catalytic oxidation performance of cobalt(II) complexes with dihydroxamic acid functionalized N-pivot lariat ethers
CHINESE CHEMICAL LETTERS
Authors: Wei, Xing-Yue; Wang, Xing-Min; Li, Ning; Qin, Sheng-Ying
Abstract
Novel Co(II) complexes with dihydroxamic acids functionalized N-pivot lariat ether CoL1-CoL4 were synthesized and characterized. Their oxygenation constants (In K-o2) and thermodynamic parameters (Delta H degrees, Delta S degrees) were measured. And their catalytic performance in oxidation of p-xylene to p-toluic acid (PTA) was investigated. The enhancement of O-2-binding and catalytic oxidation activity by the oxa aza crown ether ring of the cobalt complexes were discussed. (C) 2014 Xing-Yue Wei. Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. All rights reserved.