Oxidative stress caused by activation of NADPH oxidase 4 promotes contrast-induced acute kidney injury

Abstract

Contrast-induced acute kidney injury (CIAKI) is a leading cause of acute kidney injury following radiographic procedures. Intrarenal oxidative stress plays a critical role in CIAKI. Nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidases (Noxs) are important sources of reactive oxygen species (ROS). Among the various types of Noxs, Nox4 is expressed predominantly in the kidney in rodents. Here, we evaluated the role of Nox4 and benefit of Nox4 inhibition on CIAKI using in vivo and in vitro models. HK-2 cells were treated with iohexol, with or without Nox4 knockdown, or the most specific Nox1/4 inhibitor (GKT137831). Effects of Nox4 inhibition on CIAKI mice were examined. Expression of Nox4 in HK-2 cells was significantly increased following iohexol exposure. Silencing of Nox4 rescued the production of ROS, downregulated pro-inflammatory markers (particularly phospho-p38) implicated in CIAKI, and reduced Bax and caspase 3/7 activity, which resulted in increased cellular survival in iohexol-treated HK-2 cells. Pretreatment with GKT137831 replicated these effects by decreasing levels of phospho-p38. In a CIAKI mouse model, even though the improvement of plasma blood urea nitrogen was unclear, pretreatment with GKT137831 resulted in preserved structure, reduced expression of 8-hydroxy-2’-deoxyguanosine (8OHdG) and kidney injury molecule-1 (KIM-1), and reduced number of TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive cells. These results suggest Nox4 as a key source of reactive oxygen species responsible for CIAKI and provide a novel potential option for prevention of CIAKI.

Cocoa ameliorates renal injury in Zucker diabetic fatty rats by preventing oxidative stress, apoptosis and inactivation of autophagy

“…[30][31][32] In addition, a cocoa-diet enriched in flavanols, a procyanidin extract, epicatechin, EGCG, and procyanidin B2 have shown to suppress the oxidative stress by attenuating ROS generation, protein carbonyl content, and NOX-4 levels, and by increasing the activity of CAT and SOD antioxidant enzymes in different diabetic models. 28,[31][32][33][34][35][36] In this regard, epicatechin restored the redox status in cultured renal tubular cells subjected to a highglucose-challenge, playing NOX-4 a relevant role in this protec-tive effect; 23 indeed, inhibition of NOX-4 occurred along with increased SOD activity, reduced oxidative stress markers and improved renal functionality, 23,37 in concordance with the present results. Moreover, active Nrf2 modulates antioxidant enzymes and has demonstrated a protective effect against the diabetic kidney disease.…”

Embryonic Thermal Manipulation Affects the Antioxidant Response to Post-Hatch Thermal Exposure in Broiler Chickens

“…To maintain homeostasis, the NOX4 enzyme is heavily involved in the oxygen-sensing process, the latter of which causes it to generate significant amounts of ROS [17]. Additionally, NOX4 over-expression is often associated with oxidative stress in a number of different organs [18,53,54]. In avian muscle cells, ROS production during heat stress and subsequent oxidative damage has been tentatively attributed to NOX4 up-regulation [55].…”

Selenoprotein T protects against cisplatin‐induced acute kidney injury through suppression of oxidative stress and apoptosis

“…Currently, several evidences suggest that NADPH oxidative (Nox) is the dominant source of ROS in the kidney. [26][27][28] Therefore, we analyzed the expression of Nox in NRK-52E cells transfected with shSelT by RNA-seq. As shown in Figure 6A, SelT silencing upregulated the expression of Nox4.…”