Balogh Dora B, Hodrea Judit, Saeed Adar, Cserhalmi Marcell, Rozsahegyi Alexandra, Lakat Tamas, Lenart Lilla, Szabo Attila J, Wagner Laszlo J, Fekete Andrea
MTA-SE Lendület "Momentum" Diabetes Research Group, 1083 Budapest, Hungary.
Pediatric Center, MTA Center of Excellence, Semmelweis University, 1083 Budapest, Hungary.
Int J Mol Sci. 2024 Dec 12;25(24):13327. doi: 10.3390/ijms252413327.
Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease. Current treatments for DKD do not halt renal injury progression, highlighting an urgent need for therapies targeting key disease mechanisms. Our previous studies demonstrated that activating the Sigma-1 receptor (S1R) with fluvoxamine (FLU) protects against acute kidney injury by inhibiting inflammation and ameliorating the effect of hypoxia. Based on these, we hypothesized that FLU might exert a similar protective effect in DKD. Diabetes was induced in male Wistar rats using streptozotocin, followed by a seven-week FLU treatment. Metabolic and renal parameters were assessed along with a histological analysis of glomerular damage and fibrosis. The effects of FLU on inflammation, hypoxia, and fibrosis were tested in human proximal tubular cells and normal rat kidney fibroblasts. FLU improved renal function and reduced glomerular damage and tubulointerstitial fibrosis. It also mitigated inflammation by reducing , , and expressions and moderated the cellular response to tubular hypoxia. Additionally, FLU suppressed TGF-β1-induced fibrotic processes and fibroblast transformation. These findings suggest that S1R activation can slow DKD progression and protect renal function by modulating critical inflammatory, hypoxic, and fibrotic pathways; therefore, it might serve as a promising novel drug target for preventing DKD.
糖尿病肾病（DKD）是慢性肾病的主要病因。目前针对DKD的治疗方法无法阻止肾损伤的进展，这凸显了对靶向关键疾病机制的疗法的迫切需求。我们之前的研究表明，用氟伏沙明（FLU）激活西格玛-1受体（S1R）可通过抑制炎症和改善缺氧效应来预防急性肾损伤。基于这些，我们推测FLU可能在DKD中发挥类似的保护作用。使用链脲佐菌素诱导雄性Wistar大鼠患糖尿病，随后进行为期七周的FLU治疗。评估代谢和肾脏参数，并对肾小球损伤和纤维化进行组织学分析。在人近端肾小管细胞和正常大鼠肾成纤维细胞中测试了FLU对炎症、缺氧和纤维化的影响。FLU改善了肾功能，减少了肾小球损伤和肾小管间质纤维化。它还通过降低 、 和 的表达减轻了炎症，并减轻了细胞对肾小管缺氧的反应。此外，FLU抑制了TGF-β1诱导的纤维化过程和成纤维细胞转化。这些发现表明，激活S1R可以通过调节关键的炎症、缺氧和纤维化途径来减缓DKD的进展并保护肾功能；因此，它可能成为预防DKD的一种有前景的新型药物靶点。
