1. RAGE-mediated interstitial fibrosis in neonatal obstructive nephropathy is independent of NF-κB activation.
- Author
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Gasparitsch M, Arndt AK, Pawlitschek F, Oberle S, Keller U, Kasper M, Bierhaus A, Schaefer F, Weber LT, and Lange-Sperandio B
- Subjects
- Animals, Animals, Newborn, Apoptosis, Cadherins metabolism, Cell Proliferation, Chemotaxis, Leukocyte, Disease Models, Animal, Epithelial Cells pathology, Epithelial-Mesenchymal Transition, Fibrosis, G2 Phase Cell Cycle Checkpoints, Galectin 3 metabolism, Genotype, Intercellular Adhesion Molecule-1 genetics, Intercellular Adhesion Molecule-1 metabolism, Kidney growth & development, Kidney pathology, Kidney Diseases metabolism, Kidney Diseases pathology, Macrophages metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Receptor for Advanced Glycation End Products, Receptors, Immunologic deficiency, Receptors, Immunologic genetics, Signal Transduction, Snail Family Transcription Factors, Time Factors, Transcription Factors metabolism, Ureteral Obstruction metabolism, Ureteral Obstruction pathology, Epithelial Cells metabolism, Kidney metabolism, Kidney Diseases etiology, NF-kappa B metabolism, Receptors, Immunologic metabolism, Ureteral Obstruction complications
- Abstract
Urinary tract obstruction during nephron development causes tubular apoptosis, tubular atrophy, and interstitial fibrosis. Leukocyte recruitment is critical in the development of obstructive nephropathy leading to interstitial inflammation and renal fibrosis. RAGE, the receptor of advanced glycation end products, is implicated in chronic inflammation and has been recently identified as a novel receptor for the β2-integrin Mac-1, cooperating with ICAM-1 and thereby directly mediating leukocyte recruitment in vivo. Here, we studied the role of RAGE and ICAM-1 in a model of unilateral ureteral obstruction in neonatal mice. Interestingly, the number of infiltrating leukocytes was independent of RAGE and ICAM-1 in the ureteral obstructed neonatal kidney. By contrast, galectin-3, a marker for profibrogenic M2 macrophages, was strongly reduced in ureteral obstructed RAGE and RAGE-Icam1 knockout mice. Snail expression and loss of E-cadherin but not NF-κB activation were attenuated in both knockout models. Epithelial cell cycle arrest at G2/M, which mediates kidney fibrosis, and transforming growth factor-β expression were reduced in ureteral obstructed RAGE knockout mice. Thus, RAGE and ICAM-1 promote renal fibrosis in the developing kidney upon ureteral obstruction. Combined RAGE- and ICAM-1-blocking strategies may prove beneficial in neonatal obstructive nephropathy.
- Published
- 2013
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