Molecular Sciences I. (Poster discussion will take place in the Aula during the Coffee Break)
Akos Toth1,2; Tamas Lakat,1,2; Judit Hodrea1,2; Dora Bianka Balogh1,2; Laszlo Wagner3; Attila J. Szabo2; Andrea Fekete1, 2; Adam Hosszu1,2
1MTA-SE “Lendület” Diabetes Research Group, Budapest, Hungary
2Semmelweis University 1st Department of Pediatrics, Budapest, Hungary
3Semmelweis University Department of Transplantation and Surgery, Budapest, Hungary
4ELKH-SE Pediatrics and Nephrology Research Group, Budapest, Hungary
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 Sigma-1 receptor (S1R) agonist fluvoxamine treatment is protective against renal IRI through anti-inflammatory effects and improving renal perfusion (Hosszu et al. 2017).
The aim of this study was to investigate the renoprotective effect of specific, high affinity S1R agonists focusing on the S1R-Akt-eNOS signaling pathway and renal vasoregulation.
8 week-old male Wistar rats (n=8/group) were subjected to 50 min of unilateral ischemia with contralateral nephrectomy. 30 min before to the ischemic insult rats were treated intraperitoneally as follows: (i) isotonic saline as vehicle; (ii) highly specific, high affinity S1R agonist SA-4503 (SA); (iii) SA+ S1R antagonist NE100. Sham-operated rats were used as controls. Samples were collected 24 hours after reperfusion. Highly selective tubular injury markers (Kim1, Ngal) were evaluated. Periodic-Acid Schiff (PAS) staining was performed on kidney tissue sections to determine structural damage. Renal S1R, phospho-Akt and phospho-eNOS, Hif-1α protein levels and serum nitric oxide (NO) concentration were measured.
Renal functional parameters, blood urea nitrogen (BUN) and serum aspartate aminotransferase (AST) were reduced in the SA treated group. Expressions of early and sensitive tubular injury markers Kim1 and Ngal were less elevated in SA-treated rats. S1R, phospho-Akt and phospho-eNOS protein levels were significantly elevated in the kidneys of SA treated rats. Vasodilator nitric oxide concentration was reduced in the kidney after IRI, but returned to control levels in SA treated rats.
The specific and high affinity S1R agonist SA-4503 acts directly on proximal tubular cells by activating the S1R-NOS system. SA-4503 is renoprotective by increasing vasodilative NO production and thus improving post-ischemic renal perfusion. Based on our results activation of S1R and downstream signaling pathways could provide a novel therapeutic option in renal IRI.
Funding: OTKA PD-131637; FK-124491; LP2021-3/2021; PC2022-8/2022; TKP2021-EGA-24; UN2101GYK; KDP-2020/1019145