NFκBiz protein downregulation in acute kidney injury: Modulation of inflammation and survival in tubular cells

Acute kidney injury is characterized by decreased renal function, tubular cell death and interstitial inflammation. The transcription factor NE-kappa B is a key regulator of genes involved in cell survival and the inflammatory response. In order to better understand the regulation and role of NE-kappa B in acute kidney injury we explored the expression of NE-kappa B-related genes in experimental acute kidney injury induced by a folic acid overdose. NF kappa Biz, a member of the I kappa B family of NF-kappa B regulators encoding NF kappa Biz, was among the top up-regulated NE-kappa B-related genes at the mRNA level in experimental acute kidney injury. However, the NF kappa Biz protein was constitutively expressed by normal tubular cells but was down-regulated in experimental acute kidney injury. Kidney NF kappa Biz mRNA upregulation and protein downregulation was also observed in acute kidney injury induced by cisplatin or unilateral kidney injury resulting from ureteral obstruction. Thus, we studied the consequences of NF kappa Biz protein downregulation by specific siRNA in cultured tubular epithelial cells. NF kappa Biz mRNA and protein were up-regulated by inflammatory cytokines (IL-1 beta or TWEAK/TNE alpha/IFN gamma) and by LPS in cultured tubular cells. However, TWEAK only induced a very mild and short lived NF kappa Biz upregulation. NF kappa Biz targeting increased chemokine production and dampened Klotho downregulation induced by TWEAK, without modulating cell proliferation. NF kappa Biz targeting also rendered cells more resistant to apoptosis induced by serum deprivation or inflammatory cytokines. In conclusion, NF kappa Biz differentially regulates NF-kappa B-mediated responses of tubular cells to inflammatory cytokines in a gene-specific manner, and may be of potential therapeutic interest to limit inflammation in kidney disease. (C) 2016 Elsevier B.V. All rights reserved.