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.
Highlights
Recurrent and massive intravascular hemolysis induces renal toxicity, leading to acute kidney injury (AKI) and increasing the risk to develop chronic kidney disease (CKD) (Moreno et al, 2012; Naik et al, 2014)
We observed increased tubular cell death, determined by TUNEL staining (Figure 1B), and exacerbated oxidative stress, as determined by 4-hydroxynonenal (4-HNE) staining (Figure 1C) and presence of the endoplasmic reticulum stress markers BiP (Figure 1D) and calnexin (Figure 1E). These results suggest that kidney Hb/ iron accumulation as a consequence of intravascular hemolysis promotes oxidative stress and tubular cell injury and further activation of Nuclear factor erythroid-2-related factor 2 (Nrf2) in human disease
We demonstrate that Hb/heme accumulation in the kidney after massive intravascular hemolysis induces Nrf2 activation
Summary
Recurrent and massive intravascular hemolysis induces renal toxicity, leading to acute kidney injury (AKI) and increasing the risk to develop chronic kidney disease (CKD) (Moreno et al, 2012; Naik et al, 2014). In an oxidant milieu, hemederived iron group may be oxidized, producing hydroxyl and hydroperoxyl radicals (Gutteridge, 1986). These radicals are highly reactive and promote the formation of reactive oxygen species and subsequent lipid peroxidation and DNA damage (Jia et al, 2007; Buehler et al, 2010). Endoplasmic reticulum (ER) stress, a common form of cell stress, has recently emerged as a pathophysiologic mechanism underlying the renal damage associated with Hb and heme accumulation (Deuel et al, 2016; Feng et al, 2018).
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