The lymphotoxin β receptor is a potential therapeutic target in renal inflammation
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The lymphotoxin β receptor is a potential therapeutic target in renal inflammation. / Seleznik, Gitta; Seeger, Harald; Bauer, Judith; Fu, Kai; Czerkowicz, Julie; Papandile, Adrian; Poreci, Uriana; Rabah, Dania; Ranger, Ann; Cohen, Clemens D; Lindenmeyer, Maja; Chen, Jin; Edenhofer, Ilka; Anders, Hans J; Lech, Maciej; Wüthrich, Rudolf P; Ruddle, Nancy H; Moeller, Marcus J; Kozakowski, Nicolas; Regele, Heinz; Browning, Jeffrey L; Heikenwalder, Mathias; Segerer, Stephan.
in: KIDNEY INT, Jahrgang 89, Nr. 1, 01.2016, S. 113-26.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - The lymphotoxin β receptor is a potential therapeutic target in renal inflammation
AU - Seleznik, Gitta
AU - Seeger, Harald
AU - Bauer, Judith
AU - Fu, Kai
AU - Czerkowicz, Julie
AU - Papandile, Adrian
AU - Poreci, Uriana
AU - Rabah, Dania
AU - Ranger, Ann
AU - Cohen, Clemens D
AU - Lindenmeyer, Maja
AU - Chen, Jin
AU - Edenhofer, Ilka
AU - Anders, Hans J
AU - Lech, Maciej
AU - Wüthrich, Rudolf P
AU - Ruddle, Nancy H
AU - Moeller, Marcus J
AU - Kozakowski, Nicolas
AU - Regele, Heinz
AU - Browning, Jeffrey L
AU - Heikenwalder, Mathias
AU - Segerer, Stephan
N1 - Copyright © 2015 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
PY - 2016/1
Y1 - 2016/1
N2 - Accumulation of inflammatory cells in different renal compartments is a hallmark of progressive kidney diseases including glomerulonephritis (GN). Lymphotoxin β receptor (LTβR) signaling is crucial for the formation of lymphoid tissue, and inhibition of LTβR signaling has ameliorated several non-renal inflammatory models. Therefore, we tested whether LTβR signaling could also have a role in renal injury. Renal biopsies from patients with GN were found to express both LTα and LTβ ligands, as well as LTβR. The LTβR protein and mRNA were localized to tubular epithelial cells, parietal epithelial cells, crescents, and cells of the glomerular tuft, whereas LTβ was found on lymphocytes and tubular epithelial cells. Human tubular epithelial cells, mesangial cells, and mouse parietal epithelial cells expressed both LTα and LTβ mRNA upon stimulation with TNF in vitro. Several chemokine mRNAs and proteins were expressed in response to LTβR signaling. Importantly, in a murine lupus model, LTβR blockade improved renal function without the reduction of serum autoantibody titers or glomerular immune complex deposition. Thus, a preclinical mouse model and human studies strongly suggest that LTβR signaling is involved in renal injury and may be a suitable therapeutic target in renal diseases.
AB - Accumulation of inflammatory cells in different renal compartments is a hallmark of progressive kidney diseases including glomerulonephritis (GN). Lymphotoxin β receptor (LTβR) signaling is crucial for the formation of lymphoid tissue, and inhibition of LTβR signaling has ameliorated several non-renal inflammatory models. Therefore, we tested whether LTβR signaling could also have a role in renal injury. Renal biopsies from patients with GN were found to express both LTα and LTβ ligands, as well as LTβR. The LTβR protein and mRNA were localized to tubular epithelial cells, parietal epithelial cells, crescents, and cells of the glomerular tuft, whereas LTβ was found on lymphocytes and tubular epithelial cells. Human tubular epithelial cells, mesangial cells, and mouse parietal epithelial cells expressed both LTα and LTβ mRNA upon stimulation with TNF in vitro. Several chemokine mRNAs and proteins were expressed in response to LTβR signaling. Importantly, in a murine lupus model, LTβR blockade improved renal function without the reduction of serum autoantibody titers or glomerular immune complex deposition. Thus, a preclinical mouse model and human studies strongly suggest that LTβR signaling is involved in renal injury and may be a suitable therapeutic target in renal diseases.
KW - Adult
KW - Animals
KW - Cell Line
KW - Chemokines
KW - Disease Models, Animal
KW - Epithelial Cells
KW - Female
KW - Glomerulonephritis, IGA
KW - Humans
KW - Immunoglobulins
KW - Kidney Glomerulus
KW - Kidney Tubules
KW - Ligands
KW - Lupus Nephritis
KW - Lymphocytes
KW - Lymphotoxin beta Receptor
KW - Lymphotoxin-alpha
KW - Lymphotoxin-beta
KW - Male
KW - Mesangial Cells
KW - Mice
KW - Middle Aged
KW - RNA, Messenger
KW - Signal Transduction
KW - Transcriptome
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1038/ki.2015.280
DO - 10.1038/ki.2015.280
M3 - SCORING: Journal article
C2 - 26398497
VL - 89
SP - 113
EP - 126
JO - KIDNEY INT
JF - KIDNEY INT
SN - 0085-2538
IS - 1
ER -