Activating Nrf-2 Signaling Depresses Unilateral Ureteral Obstruction-Evoked Mitochondrial Stress-Related Autophagy, Apoptosis and Pyroptosis in Kidney

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.

LIM homeobox transcription factor 1B expression affects renal interstitial fibrosis and apoptosis in unilateral ureteral obstructed rats

“…Furthermore, Kida et al and Sato et al determined that a positive linear relationship exists between tubular dilatation and tubular epithelial apoptosis in UUO mice (18). Increased ROS, lipid peroxidation, and compromised antioxidants were previously found in a number of studies using obstructed rodent kidneys (6,24,35,48), and ROS have been suggested to impair the integrity of the glomerular basement membrane, reduce podocyte proteoglycan de novo synthesis, and stimulate factors promoting ECM deposition, including TGF-␤ 1 (9), as similarly observed in the present study. Overall, these results corroborate our results in the RTEC model system.…”

Nrf2 protects mitochondrial decay by oxidative stress

“…As a transcription factor, Nrf2 can regulate the expression of autophagy adaptor protein NDP52 and p62/SQSTM1, presumably facilitating autophagy (51,52). However, knocking down Nrf2 resulted in an increase of autophagy, suggesting a suppressive role of Nrf2 in autophagy (53)(54)(55). Although suppression of mitophagy may contribute to an inhibition of mitochondrial loss, a deficit in mitophagy results in the accumulation of dysfunctional mitochondria characterized by mitochondrial swelling, loss of cristae structure, decreased membrane potential, and decreased capacity for metabolism (56,57).…”

Regulated Cell Death in AKI

“…[144][145][146][147] The unique feature of pyroptosis compared with other pathways of regulated necrosis is the maturation of proinflammatory cytokines during the cell death process, [148][149][150] which depends on cleavage mediated by nonapoptotic caspases. Many of the in vivo studies on pyroptosis have been performed in caspase 1-deficient mice, which have been described to carry a passenger mutation that functionally renders them caspase 1/11 double-deficient.…”