Introduction and aims: Diabetic kidney disease (DKD) is a major health concern among diabetic patients. Current therapies cannot halt the progression of renal failure; thus, the development of additional novel therapies is of paramount importance. We previously showed that the Sigma-1 receptor (S1R) agonism is protective in acute kidney injury (AKI). Inflammation and tubular hypoxia are key processes in the pathogenesis of DKD. S1R agonist treatment inhibits these pathologic pathways in AKI, therefore we assume that a similar protective effect can be shown in DKD as well.

Methods: Diabetes mellitus (DM) was induced by streptozotocin (65 mg/bwkg, ip.) in adult, male Wistar rats and they were treated for seven weeks with fluvoxamine (D+FLU, 20 mg/bwkg/day, po.). Metabolic parameters, renal function, and histology were evaluated. Inflammation was tested in lipopolysaccharide-stimulated (LPS, 1 µg/mL) human proximal tubular epithelial cells (HK-2). To test hypoxia cells were placed in a hypoxic chamber (1% O2, 2h). Cells were treated with 10 µM FLU. Proinflammatory and hypoxia markers were measured.

Results: Renal function (BUN: DM: 26.6±2.42 vs. DM+FLU: 17.3±2.30 mmol/L; Serum creatinine: DM: 42.0±2.39 vs.DM+FLU: 34.5±2.74 µmol/L; Proteinuria: DM: 42.5±6.38 vs. DM+FLU: 21.5±4.99 mg/mL; p<0.05), structural damage (PAS staining), and fibrotic tissue accumulation (Masson’s trichrome staining) were reduced by FLU. FLU decreased LPS-induced IL6, TLR4, and NFKB1 expressions in HK-2 cells. Hypoxia-induced HIF1A and HIF2A elevation were suspended by FLU treatment. Moreover, VEGFA and SLC2A1 expressions were also increased in hypoxia and FLU prevented their elevation.

Conclusions: Activation of S1R slows the progression of chronic renal impairment in DKD. Moreover, S1R agonist FLU prevents hypoxic and inflammatory damage in HK-2 cells, which may explain the molecular mechanisms behind its renoprotective effect. We propose S1R as a novel target for the prevention of DKD.


D. B. Balogh: None. L. Lenart: None. A. Hosszu: None. A. Saeed: None. J. Hodrea: None. A. R. Toth: None. A. J. Szabo: None. A. Fekete: None.


National Research, Development and Innovation Fund (UNKP-22-4-II-SE-2, TKP2021-EGA-24); Hungarian Academy of Sciences (LP2021-3/2021)

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