CHOP deficiency results in elevated lipopolysaccharide-induced inflammation and kidney injury

Esposito V, Grosjean F, Tan J, Huang L, Zhu L, Chen J, Xiong H, Striker GE, Zheng F. CHOP deficiency results in elevated lipopolysaccharide-induced inflammation and kidney injury. Am J Physiol Renal Physiol 304: F440-F450, 2013. First published December 12, 2012; doi:10.1152/ajprenal.00487.2011.-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-alpha 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-kappa B 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.