Hemin modulates hypoxia-induced endoplasmic reticulum stress, through a p38 MAPK-dependent signaling pathway, in renal tubular cells

Abstract

Ischemia and reperfusion injury (IRI) remains a challenging clinical problem, especially in hospitalized patients, and one of the primary aggravators of this insult is inflammation. Endoplasmic reticulum stress (ERS) appears to be an important mediator of this process, leading to the unfolded protein response (UPR), which ultimately aims to alleviate the aggression but could eventually lead to cell death, if ERS is prolonged. Hemin-treatment induces the production of heme oxygenase-1 (HO-1), an enzyme with anti-inflammatory, anti-apoptotic and immunomodulatory properties. Hemin-treatment generates beneficial byproducts, such as carbon monoxide, free iron and biliverdin, that could potentially attenuate ERS. In this study, we explored the role of hemin as a modulatory substance in the protection against ERS-induced lesions prior to both thapsigargin treatment and oxygen and glucose deprivation (OGD) in in vitro systems and in the protection against IRI in an in vivo model of disease. First, we observed that pretreatment with hemin resulted in reduced cell death, decreased expression of inflammatory cytokines, such as TNF-α and IL-6, and reduced ERS, reflected by reductions in BiP, p-eif2α, and chop expression, throughout the evaluated period. Additionally, we observed that lesions triggered by IRI were also modulated by hemin-pretreatment, reflected by reduced renal dysfunction, decreased apoptosis, reduced inflammation and a reduction in ERS markers. Moreover, we verified that the mechanism involved in this protection appears to be mediated by the p38 MAPK pathway, as blockade of this pathway led to the abrogation of the observed protection. We conclude that hemin-pretreatment results in the attenuation of ERS and a reduction in inflammation. Our data further suggests that p38 MAPK could be a valuable therapeutic target for the prevention of renal dysfunction following ischemia.