Involvement of NF-κBIZ and related cytokines in age-associated renal fibrosis

Abstract

Chronic inflammation is a major contributor to age-related nephropathic changes, including renal fibrosis. In this study, various experimental paradigms were designed to delineate the role played by NF-?BIZ (also known as I?B?) in age-associated renal fibrosis. Analyses based on RNA-sequencing findings obtained by next generation sequencing (NGS) revealed the upregulations of NF-?BIZ and of IL-6 and MCP-1 (both known to be regulated by NF-?BIZ) during aging. The up-regulation of NF-?BIZ in aged rat kidneys coincided with increased macrophage infiltration. In LPS-treated macrophages, oxidative stress was found to play a pivotal role in NF-?BIZ expression, suggesting age-related oxidative stress is associated with NF-?BIZ activation. Furthermore, these in vitro findings were confirmed in LPS-treated old rats, which showed higher levels of oxidative stress and NF-?BIZ in kidneys than LPS-treated young rats. Additional in vitro experiments using macrophages and kidney fibroblasts demonstrated NF-?BIZ and related cytokines participate in fibrosis. In particular, increased levels of NF-?BIZ-associated cytokines in macrophages significantly up-regulated TGF-β induced kidney fibroblast activation. Moreover, experiments with NF-?BIZ knocked down macrophages showed reduced TGF-β- induced kidney fibroblast activation. The findings of the present study provide evidence regarding an involvement of NF-?BIZ in age-associated progressive renal fibrosis and provides potential targets for its prevention.

High Uric Acid-Induced Epithelial-Mesenchymal Transition of Renal Tubular Epithelial Cells via the TLR4/NF-kB Signaling Pathway

“…The NF-κB is extensively expressed in renal glomerular cells and renal tubular epithelial cells. The activation of NF-κB can mediate inflammatory response, promote renal tubular epithelial cells turn into fibroblasts cells, and upregulate the expression of a variety of inflammatory factors and chemokines including IL-6, IL-1β, and TNF-α, which results in the promotion of immune inflammatory reaction and renal tubule interstitial fibrosis [33, 34]. Our results found that UA could activate TLR4/NF-кB signaling pathways and induce EMT of renal tubular epithelial cells.…”

NOX1-derived ROS drive the expression of Lipocalin-2 in colonic epithelial cells in inflammatory conditions

“…However, our findings are in agreement with the observation that oxidative stress is associated with upregulation of IκBζ. 45 Contrary to IκBζ, activation of NF-κB was not dependent on ROS in colonic epithelial cells, as neither NAC nor DPI inhibited the phosphorylation of NFκB-p65. In accordance with this, we found that chemokine synthesis, in particular IL-8, which expression is under the control of NF-kB, was not inhibited by DPI in colonic epithelial cells co-stimulated by TNFα and IL-17.…”

MMP2-A2M interaction increases ECM accumulation in aged rat kidney and its modulation by calorie restriction

“…However, there are still numerous challenges in relation to fully describing this complex biological process [ 18 ]. It has been recently suggested that aging is associated with progressive ECM accumulation which involves loss of function in several tissues [ 19 - 22 ]. Because kidney is one of the most vulnerable tissues which can be influenced by aging and age-related physiological changes, it also shows time-dependent accumulation of ECM in the glomerulus and interstitial parts followed by fibrosis [ 6 , 23 ].…”