title: RAGE-mediated interstitial fibrosis in neonatal obstructive nephropathy is independent of NF-κB activation.
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.
authors.affiliation: Department of Pediatrics, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Mojca
authors.initials: M
authors.lastname: Gasparitsch
authors.forename: Anne-Karin
authors.initials: AK
authors.lastname: Arndt
authors.forename: Felix
authors.initials: F
authors.lastname: Pawlitschek
authors.forename: Stephan
authors.initials: S
authors.lastname: Oberle
authors.forename: Ursula
authors.initials: U
authors.lastname: Keller
authors.forename: Michael
authors.initials: M
authors.lastname: Kasper
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Franz
authors.initials: F
authors.lastname: Schaefer
authors.forename: Lutz T
authors.initials: LT
authors.lastname: Weber
authors.forename: Bärbel
authors.initials: B
authors.lastname: Lange-Sperandio
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism; D049109:Cell Proliferation; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis; D059565:G2 Phase Cell Cycle Checkpoints; D037502:Galectin 3 / Q000378:metabolism; D005838:Genotype; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D010641:Phenotype; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications* / Q000378:metabolism / Q000473:pathology
chemical_list: D015820:Cadherins; D037502:Galectin 3; C090509:Icam1 protein, mouse; C485095:Lgals3 protein, mouse; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D018799:Intercellular Adhesion Molecule-1