Abstract
Exacerbated oxidative stress and inflammation may induce three types of programmed cell death, autophagy, apoptosis and pyroptosis in unilateral ureteral obstruction (UUO) kidney. Sulforaphane activating NF-E2-related nuclear factor erythroid-2 (Nrf-2) signaling may ameliorate UUO-induced renal damage. UUO was induced in the left kidney of female Wistar rats. The level of renal blood flow, cortical and medullary oxygen tension and reactive oxygen species (ROS) was evaluated. Fibrosis, ED-1 (macrophage/monocyte) infiltration, oxidative stress, autophagy, apoptosis and pyroptosis were evaluated by immunohistochemistry and Western blot in UUO kidneys. Effects of sulforaphane, an Nrf-2 activator, on Nrf-2- and mitochondrial stress-related proteins and renal injury were examined. UUO decreased renal blood flow and oxygen tension and increased renal ROS, 3-nitrotyrosine stain, ED-1 infiltration and fibrosis. Enhanced renal tubular Beclin-1 expression started at 4 h UUO and further enhanced at 3d UUO, whereas increased Atg-5-Atg12 and LC3-II expression were found at 3d UUO. Increased renal Bax/Bcl-2 ratio, caspase 3 and PARP fragments, apoptosis formation associated with increased caspase 1 and IL-1β expression for pyroptosis formation were started from 3d UUO. UUO reduced nuclear Nrf-2 translocation, increased cytosolic and inhibitory Nrf-2 expression, increased cytosolic Bax translocation to mitochondrial and enhanced mitochondrial Cytochrome c release into cytosol of the UUO kidneys. Sulforaphane significantly increased nuclear Nrf-2 translocation and decreased mitochondrial Bax translocation and Cytochrome c release into cytosol resulting in decreased renal injury. In conclusion, sulforaphane via activating Nrf-2 signaling preserved mitochondrial function and suppressed UUO-induced renal oxidative stress, inflammation, fibrosis, autophagy, apoptosis and pyroptosis.
Highlights
Obstruction of the upper urinary tract has deleterious effects on the kidney
We further suggest that enhancements in nuclear nuclear factor erythroid-2 (Nrf-2) translocation and prevention in mitochondrial Cytochrome c release to cytosol may attenuate reactive oxygen species (ROS)-triggered autophagy, apoptosis and pyroptosis in the ureteral obstruction (UUO) kidney
According to our data and previous studies1–3,24, UUO is characterized with a gradually decreased renal blood flow and cortical and medullary oxygen tension and subsequently enhanced renal ROS in a time-dependent manner (Figure 1). These led to the increases in tubulointerstitial inflammation (ED-1 infiltration), fibrosis, autophagy, apoptosis and pyroptosis in the damaged kidneys
Summary
Obstruction of the upper urinary tract has deleterious effects on the kidney. The histological derangements associated with obstruction are localized primarily in the tubulointerstitial areas of the kidney and include massive tubular dilation, apoptotic tubular cell deletion, and progressive tubulointerstitial fibrosis [1,2]. Unilateral ureteral obstruction (UUO), a well-characterized hydronephrosis model, demonstrates a depressed renal blood flow in the obstructed kidney [2]. Increased toxic reactive oxygen species (ROS) accumulation leading to tubulointerstitial injury is frequently recognized in various kinds of kidney diseases [3,4]. The excess ROS evoke abnormal signal transduction, cellular dysfunction, inflammatory monocyte/macrophage (ED-1) infiltration and cell death cascade in the damaged kidneys [2,3,5]
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