title: CHOP deficiency results in elevated lipopolysaccharide-induced inflammation and kidney injury.
abstract: 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 LPS-induced increase of CHOP in kidneys may inhibit inflammatory response in renal cells and provide protection against AKI.
authors.affiliation: Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Esposito
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Grosjean
authors.forename: Jianming
authors.initials: J
authors.lastname: Tan
authors.forename: Liangfu
authors.initials: L
authors.lastname: Huang
authors.forename: Libing
authors.initials: L
authors.lastname: Zhu
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.forename: Huabao
authors.initials: H
authors.lastname: Xiong
authors.forename: Gary E
authors.initials: GE
authors.lastname: Striker
authors.forename: Feng
authors.initials: F
authors.lastname: Zheng
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D005260:Female; D007249:Inflammation / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D007678:Kidney Glomerulus / Q000502:physiology; D008070:Lipopolysaccharides; D017737:Macrophages, Peritoneal / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D050199:Podocytes / Q000502:physiology; D018805:Sepsis / Q000150:complications*; D013312:Stress, Physiological; D051742:Transcription Factor CHOP / Q000172:deficiency* / Q000235:genetics
chemical_list: D008070:Lipopolysaccharides; D051742:Transcription Factor CHOP