The activation of nuclear factor-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling blunts cholestasis-induced liver and kidney injury

Abstract

Cholestasis is a severe clinical complication that severely damages the liver. Kidneys are also the most affected extrahepatic organs in cholestasis. The pivotal role of oxidative stress has been mentioned in the pathogenesis of cholestasis-induced organ injury. The activation of the nuclear factor-E2-related factor 2 (Nrf2) pathway is involved in response to oxidative stress. The current study was designed to evaluate the potential role of Nrf2 signaling activation in preventing bile acids-induced toxicity in the liver and kidney. Dimethyl fumarate was used as a robust activator of Nrf2 signaling. Rats underwent bile duct ligation surgery and were treated with dimethyl fumarate (10 and 40 mg/kg). Severe oxidative stress was evident in the liver and kidney of cholestatic animals (P < 0.05). On the other hand, the expression and activity of Nrf2 and downstream genes were time-dependently decreased (P < 0.05). Moreover, significant mitochondrial depolarization, decreased ATP levels, and mitochondrial permeabilization were detected in bile duct-ligated rats (P < 0.05). Histopathological alterations included liver necrosis, fibrosis, inflammation and kidney interstitial inflammation, and cast formation. It was found that dimethyl fumarate significantly decreased hepatic and renal injury in cholestatic animals (P < 0.05). Based on these data, the activation of the cellular antioxidant response could serve as an efficient therapeutic option for managing cholestasis-induced organ injury.

Protective antioxidative and anti-inflammatory actions of β-caryophyllene against sulfasalazine-induced nephrotoxicity in rat

“…[24][25][26][27] In contrast, Nrf2 is a ubiquitous protein that protects against oxidative stress-induced renal damage by promoting the expression of several antioxidant enzymes. 28,29 Likewise, the activation of renal AMPK/AKT pathway attenuates cell injury associated with oxidative stress and inflammation. [30][31][32] To the best of our knowledge, this report is the first to unveil substantial increases in NF-κB, TGF-β1, and KIM-1 genes and proteins, while those of AMPK-α, AKT1, and Nrf2 declined, in the PC renal specimens in comparison with the NC rats.…”

“…24–27 In contrast, Nrf2 is a ubiquitous protein that protects against oxidative stress-induced renal damage by promoting the expression of several antioxidant enzymes. 28,29 Likewise, the activation of renal AMPK/AKT pathway attenuates cell injury associated with oxidative stress and inflammation. 30–32…”

“…Hence, we suggest that the pathogenesis of SFZ-induced renal inflammation and oxidative stress could involve overexpression of NF-κB and TGF-β1 with simultaneous inhibition of AMPK-α, AKT1, and Nrf2 genes and proteins that subsequently initiate apoptosis by elevating Casp-3. 9,25,26,28,30 Moreover, we propose that KIM-1, which is a sensitive and specific marker of tubular damage, could be used to monitor SFZ-induced nephrotoxicity. 33,34 However, additional studies should further investigate the molecular mechanisms that turn SFZ from an anti-inflammatory drug to an inducer of renal inflammatory reactions to corroborate our propositions.…”

Antioxidative and Anti-Inflammatory Protective Effects of β-Caryophyllene against Amikacin-Induced Nephrotoxicity in Rat by Regulating the Nrf2/AMPK/AKT and NF-κB/TGF-β/KIM-1 Molecular Pathways

“…Furthermore, both molecules also increased substantially in rat renal tissues with gentamicin treatment, which is another aminoglycoside antibiotic linked with renal injury [36]. On the other hand, Nrf2 is a key molecule that regulates cellular antioxidant pathways, and the protein decreases significantly in renal tissues with a variety of diseases induced by oxidative stress [37,38]. Additionally, curcumin attenuated gentamycin-induced renal injury by increasing the production of Nrf2 [39].…”

Pentoxifylline mitigates cholestasis-related cholemic nephropathy

“…We used male Sprague-Dawley (SD) rats (250-300 g) that are usually used for investigating the adverse effects of cholestasis on the kidney [ 26 , 27 ]. Animals were purchased from Shiraz University of Medical Sciences, Shiraz, Iran.…”