TY - JOUR
T1 - CHOP deficiency results in elevated lipopolysaccharide-induced inflammation and kidney injury
AU - Esposito, Vittoria
AU - Grosjean, Fabrizio
AU - Tan, Jianming
AU - Huang, Liangfu
AU - Zhu, Libing
AU - Chen, Jian
AU - Xiong, Huabao
AU - Striker, Gary E.
AU - Zheng, Feng
PY - 2013/2/15
Y1 - 2013/2/15
N2 - C/EBP homologous protein (CHOP) is an important mediator of endoplasmic reticulum (ER) stress-induced cell and organ injury. Here we show that lipopolysaccharide (LPS)-induced acute kidney injury (AKI) is associated with ER stress and elevated CHOP. We postulated that CHOP-/- mice would be protected against LPS-induced-AKI. Unexpectedly, while Toll-like receptor 4 (TLR4) expression levels were comparable in kidneys of CHOP-/- and wild-type (WT) mice, CHOP-/- mice developed more severe AKI after LPS injection. Furthermore, the severe kidney injury in CHOP-/- mice was associated with an exaggerated inflammatory response. Serum TNF-α levels were more elevated in LPS-treated CHOP-/- mice. There was a 3.5-fold higher amount of renal neutrophil infiltrates in LPS-treated CHOP-/- than in WT mice. Additionally, the kidneys of LPS-treated CHOP-/- mice had a more prominent increase in NF-κB activation and further upregulation of proinflammatory genes, i.e., c-x-c motif ligand 1 (CXCL-1), macrophage inflammatory protein-2 (MIP-2), and IL-6. Finally, proximal tubules, glomeruli, and podocytes isolated from CHOP-/- mice also had an exaggerated proinflammatory response to LPS. Since LPS directly increased CHOP in glomeruli and podocytes of WT mice, together these data suggest that the LPSinduced increase of CHOP in kidneys may inhibit inflammatory response in renal cells and provide protection against AKI.
AB - C/EBP homologous protein (CHOP) is an important mediator of endoplasmic reticulum (ER) stress-induced cell and organ injury. Here we show that lipopolysaccharide (LPS)-induced acute kidney injury (AKI) is associated with ER stress and elevated CHOP. We postulated that CHOP-/- mice would be protected against LPS-induced-AKI. Unexpectedly, while Toll-like receptor 4 (TLR4) expression levels were comparable in kidneys of CHOP-/- and wild-type (WT) mice, CHOP-/- mice developed more severe AKI after LPS injection. Furthermore, the severe kidney injury in CHOP-/- mice was associated with an exaggerated inflammatory response. Serum TNF-α levels were more elevated in LPS-treated CHOP-/- mice. There was a 3.5-fold higher amount of renal neutrophil infiltrates in LPS-treated CHOP-/- than in WT mice. Additionally, the kidneys of LPS-treated CHOP-/- mice had a more prominent increase in NF-κB activation and further upregulation of proinflammatory genes, i.e., c-x-c motif ligand 1 (CXCL-1), macrophage inflammatory protein-2 (MIP-2), and IL-6. Finally, proximal tubules, glomeruli, and podocytes isolated from CHOP-/- mice also had an exaggerated proinflammatory response to LPS. Since LPS directly increased CHOP in glomeruli and podocytes of WT mice, together these data suggest that the LPSinduced increase of CHOP in kidneys may inhibit inflammatory response in renal cells and provide protection against AKI.
KW - CHOP
KW - ER stress
KW - Glomeruli
KW - Inflammation
KW - Podocytes
KW - Proximal tubules
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U2 - 10.1152/ajprenal.00487.2011
DO - 10.1152/ajprenal.00487.2011
M3 - Article
C2 - 23235477
AN - SCOPUS:84874077537
VL - 304
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 0363-6119
IS - 4
ER -