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.
Highlights
Iodinated contrast medium (CM)-induced acute kidney injury (CIAKI) is an acute deterioration of renal function following administration of CM in the absence of any other known reason [1] Contrast-induced acute kidney injury (CIAKI) remains the leading cause of iatrogenic acute kidney injury (AKI) following radiographic procedures
We further examined the effects of iohexol on cellular Nox4 mRNA and protein expression in cultured HK-2 cells
We showed that exposure of renal proximal tubular cells to CM resulted in significant increases in Nox4 expression and activity with increased reactive oxygen species (ROS)
Summary
Iodinated contrast medium (CM)-induced acute kidney injury (CIAKI) is an acute deterioration of renal function following administration of CM in the absence of any other known reason [1] CIAKI remains the leading cause of iatrogenic acute kidney injury (AKI) following radiographic procedures. It has been suggested that CM increases osmotic load, decreases renal blood flow, and induces renal arterial constriction. Such a condition promotes generation of ROS and results in ischemic tubular injury, and can be a reason for direct tubular toxicity [1, 9]. As no effect on Nox or Nox protein expression was observed for GKT137831, it appears to target the enzymatic activity of Nox and Nox1 [15, 16] Based on these observations, we investigated the role of Nox and the benefit of inhibition of Nox using in vivo and in vitro models of CIAKI
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