PhD Scientific Days 2022

Clinical Medicine VII. (Poster discussion will take place in the Aula during the Coffee Break)

The Sigma-1 Receptor-Mediated Role of 17β-estradiol in in vitro models of Renal Ischemia Reperfusion Injury

Text of the abstract

Introduction: It is a known phenomenon that females enjoy a reduced susceptibility to renal ischemia/reperfusion injury (IRI) compared to males. We recently showed that Sigma-1 receptor (S1R) activation by 17β-estradiol in female rats is protective in IRI by enhancing the heat shock response.
Aims: In the present study we aimed to investigate the molecular pathways induced by the 17β-estradiol mediated activation of sigma-1 receptor in various in vitro models.
Methods: Human renal proximal tubular epithelial cells (HK-2) were treated with 17β-estradiol (E2) for 24 h. The treated HK-2 cells were stimulated by layering mineral oil (45 min at 37C), hydrogen peroxide (H2O2, 500 μM, 2 h) and Tunicamycin (Tm, 5 nM, 6 h) to induce the hypoxia stress, oxidative stress and ER stress resp.
Results: Hypoxic injury of HK-2 cells was confirmed by elevated HIF-1α protein levels and HMOX1 gene expression. Both HIF-1 and HMOX1 levels were decreased following E2 therapy, indicating reduced hypoxia. Cell proliferation markers, Proliferating cell nuclear antigen (PCNA) and Ki67 are reduced tendency after hypoxia, which was counteracted by E2. Both proinflammatory cytokines IL-1β and IL-6 increased after hypoxia and E2 treatment minimized IL-1β expression. H2O2 induced the oxidative stress by elevating HMOX1, p53-mediated apoptotic pathway and inflammatory cytokines which were abated by E2 treatment. CHOP expression increased sevenfold following tunicamycin (Tm) therapy, but was unaffected by E2. PCNA and Ki67 levels were lowered by ER stress but were restored to control levels following E2 treatment. ER stress enhanced acute phase inflammatory cytokines.
Conclusions: We identified S1R activation by E2 as a possible mediator of protective mechanisms against hypoxic- oxidative- and ER-stress in renal proximal tubular cells. Based on our data S1R activation could provide a new option for renoprotective therapy.

Funding: OTKA PD-131637; FK-124491; LP2021-3/2021; PC2022-8/2022; TKP2021-EGA-24; UN2101GYK; KDP-2020/1019145