Nrf2 Plays a Protective Role Against Intravascular Hemolysis-Mediated Acute Kidney Injury

Abstract

Massive intravascular hemolysis is associated with acute kidney injury (AKI). Nuclear factor erythroid-2-related factor 2 (Nrf2) plays a central role in the defense against oxidative stress by activating the expression of antioxidant proteins. We investigated the role of Nrf2 in intravascular hemolysis and whether Nrf2 activation protected against hemoglobin (Hb)/heme-mediated renal damage in vivo and in vitro . We observed renal Nrf2 activation in human hemolysis and in an experimental model of intravascular hemolysis promoted by phenylhydrazine intraperitoneal injection. In wild-type mice, Hb/heme released from intravascular hemolysis promoted AKI, resulting in decreased renal function, enhanced expression of tubular injury markers (KIM-1 and NGAL), oxidative and endoplasmic reticulum stress (ER), and cell death. These features were more severe in Nrf2-deficient mice, which showed decreased expression of Nrf2-related antioxidant enzymes, including heme oxygenase 1 (HO-1) and ferritin. Nrf2 activation with sulforaphane protected against Hb toxicity in mice and cultured tubular epithelial cells, ameliorating renal function and kidney injury and reducing cell stress and death. Nrf2 genotype or sulforaphane treatment did not influence the severity of hemolysis. In conclusion, our study identifies Nrf2 as a key molecule involved in protection against renal damage associated with hemolysis and opens novel therapeutic approaches to prevent renal damage in patients with severe hemolytic crisis. These findings provide new insights into novel aspects of Hb-mediated renal toxicity and may have important therapeutic implications for intravascular hemolysis-related diseases.

Formation and Detection of Highly Oxidized Hemoglobin Forms in Biological Fluids during Hemolytic Conditions

“…Besides CSF analysis, we used a well-established model of acute sterile hemolysis to investigate the formation of the different Hb species in vivo. In agreement with previous observations [27,50,51], we found that the injection of PHZ triggered a marked elevation of extracellular heme content in the plasma. The determination of the distribution of the extracellular heme among the different redox states of Hb revealed that Hb dominates at an early time point (4 h), and hemichrome becomes more dominant at later time points.…”

Andrade-Oliveira Salvianolic Acid B Modulates Caspase-1–Mediated Pyroptosis in Renal Ischemia-Reperfusion Injury via Nrf2 Pathway

“…Previous studies have indicated that the Nrf2 signaling pathway plays a key role in inflammatory responses and oxidative stress during I/R. Nrf2 knockout increases the level of oxidative stress in AKI and exacerbates the ischemic injury, which, when activated, inhibits ROS levels and reduces AKI kidney damage ( Rubio-Navarro et al, 2019 ). Consistently, the increased expression of MDA, SOD and GSH in I/R mice reflects the increase in oxidative stress levels, and SalB treatment has a significant improvement effect, especially in the high-dose group.…”

13-Acetoxysarcocrassolide Exhibits Cytotoxic Activity against Oral Cancer Cells through the Interruption of the Keap1/Nrf2/p62/SQSTM1 Pathway: The Need to Move Beyond Classical Concepts

“…The Keap1/Nrf2/p62/SQSTM1 signaling pathway is a major defense mechanism for oxidative stress [29][30][31]. Recent studies indicated that p62/SQSTM1 is a target gene of the transcription factor Nrf2 [32,33].…”