PhD Scientific Days 2026

Poster Session 1.I - Theoretical and Translational Medicine

Protective effects of a novel Sigma-1 receptor agonist in renal ischemia/reperfusion injury

Name of the presenter

Tóth, Ákos

Institute/workplace of the presenter

MTA-SE Lendület “Momentum” Diabetes Research Group, Budapest, Hungary; Pediatric Center MTA Center of Excellence, Semmelweis University, Budapest, Hungary;

Authors

Akos Roland Toth¹, Tamas Lakat², Andras Budai³, Hanga Kallay^2,4, Balint Szokol⁵, Laszlo J. Wagner⁶, Laszlo Orfi⁵, Marcell Kreko⁵, Attila J. Szabo⁴, Andrea Fekete^2,4, Adam Hosszu^2,4
1: MTA-SE Lendület “Momentum” Diabetes Research Group, Budapest, Hungary; Pediatric Center MTA Center of Excellence, Semmelweis University, Budapest, Hungary;
2: MTA-SE Lendület “Momentum” Diabetes Research Group, Budapest, Hungary
3: Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Budapest, Hungary
4: Pediatric Center MTA Center of Excellence, Semmelweis University, Budapest, Hungary
5: Vichem Chemie Research Ltd – Veszprem, Hungary
6: Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary

Text of the abstract

Introduction
Renal ischemia/reperfusion injury (IRI)-induced acute kidney injury is associated with high mortality and morbidity, and effective therapies are lacking. We previously showed that the Sigma-1 receptor (S1R) agonist fluvoxamine is protective against renal IRI.
Aims
In this study, we developed a new fluvoxamine analog compound (VCC) with limited blood-brain barrier penetration, and we aimed to test the renoprotective effect of the VCC in a murine model of renal IRI. Furthermore, we identified the molecular mechanisms triggered by S1R activation.
Methods
6-week-old male C57BL/6J (wild-type) and S1R knock-out (S1R-/-) mice were subjected to 25 min of unilateral ischemia with contralateral nephrectomy. 30 min before the ischemic insult, mice were treated i.p. as follows: isotonic saline as vehicle (IRI) or VCC (IRI+VCC). Sham-operated animals that underwent the same surgical procedures without clamping were used as controls (Sham). 24 and 48 h after the reperfusion, serum and kidney samples were collected. Renal functional parameters (blood urea nitrogen (BUN) and serum creatinine (Scr)) and tubular injury markers (Kim1 and Ngal) were measured. Structural damage was assessed on PAS-stained kidney sections. Expressions of inflammatory (Il1β, Tnfα) and apoptotic (Bax, P53, Caspase 3) genes were investigated.
Results
VCC markedly alleviated BUN and serum creatinine levels, KIM-1 and NGAL expression, and structural damage at both 24 and 48 h after reperfusion in wild-type animals. Neither renal functional parameters nor tubular injury markers nor PAS-stained histological assessments indicated any renoprotective effect of S1R agonist VCC in S1R -/- mice. S1R activation by VCC modulated apoptotic processes by inhibiting the p53-Bax pathway. Moreover, VCC regulated CaMKII-NF-κB signaling, thereby reducing proinflammatory cytokine expression.
Conclusion
S1R activation by VCC alleviates renal IRI by suppressing apoptotic and inflammatory pathways. Notably, the absence of protective effects in S1R knockout animals indicates that these renoprotective actions are specifically mediated through S1R signaling. Together, these findings underscore the therapeutic potential of targeting S1R to mitigate ischemic kidney injury.
Funding
LP2021-3/2021, TKP2021-EGA-24, STAGE 2024-1.2.3-HU-RIZONT-2024-00056