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.

Inactivation of C/ebp Homologous Protein-driven Immune-Metabolic Interactions Exacerbate Obesity and Adipose Tissue Leukocytosis

“…During lipopolysaccharide-induced lung injury, Chop knock-out animals are protected against inflammatory damage (25). However, during lipopolysaccharide-induced kidney injury, Chop deficiency exacerbates kidney inflammation and damage, similar to the results we found in adipose tissue (26). The reason for heterogeneity of tissue response to Chop ablation is unclear, yet this may explain the protective aspects of Chop ablation on the pancreatic beta cells and the detrimental effects of whole body Chop deletion in response to a HFD.…”

Naltrexone attenuates endoplasmic reticulum stress induced hepatic injury in mice

“…to abnormalities in insulin function, inflammatory and immune responses and apoptosis (8,30). ER stress has been induced in various tissues of obese mice and humans (16,30,34).…”

Protective effects of aliskiren and valsartan in mice with diabetic nephropathy

“…increased expression of CHOP and XBP-1). [43][44][45] Although the role of a classical marker of ER stress C/EBP homologous protein (CHOP), a transcription factor induces apoptosis, in kidney injury is debatable, 46 CHOP deficient mice were resistant to ER stress-induced cell death and DN, 45 and consistent with this, expression of CHOP protein was significantly increased in diabetic mice when compared with controls. In the present study aliskiren with or without valsartan reduced CHOP and XBP-1 protein expression, thus may attenuate ER stress response and prevent cells from injury and apoptosis in diabetic kidneys.…”