Department of Nephrology, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China.
Department of Nephrology, Jingan District Central Hospital/Jingan Branch, Huashan Hospital affiliated to Fudan University, Shanghai, 200040, China.
J Nat Med. 2018 Mar;72(2):390-398. doi: 10.1007/s11418-017-1152-z. Epub 2017 Dec 19.
Renal ischemia reperfusion injury (RIRI) refers to the irreversible damage for renal function when blood perfusion is recovered after ischemia for an extended period, which is common in clinical surgeries and has been regarded as a major risk for acute renal failures (ARF) that is accompanied with unimaginably high morbidity and mortality. Hypoxia during ischemia followed by reoxygenation via reperfusion serves as a major event contributing to cell apoptosis, which has been widely accepted as the vital pathogenesis in RIRI. Preventing apoptosis in renal tubular epithelial cell has been considered as effective method for blocking RIRI. In this paper, we established a hypoxia/reoxygenation (H/R) injury model in human proximal tubular epithelial HK-2 cells. Here, we found increased SPHK1 levels in H/R injured HK-2 cells, which could be significantly down regulated after berberine treatment. Berberine has been reported to exert a protective effect on H/R-induced apoptosis of HK-2 cells. So, in our present study, we planned to investigate whether SPHK1 participated in the anti-apoptosis process of berberine in H/R injured HK-2 cells. Our study confirmed the protective effect of berberine against H/R-induced apoptosis in HK-2 cells through promoting cells viability, inhibiting cells apoptosis, and down-regulating p-P38, caspase-3, caspase-9 as well as SPHK1, while up regulating the ratio of Bcl-2/Bax. However, SPHK1 overexpression in HK-2 cells induced severe apoptosis, which can be significantly ameliorated with additional berberine treatment. We concluded that berberine could remarkably prevent H/R-induced apoptosis in HK-2 cells through down-regulating SPHK1 expression levels, and the mechanisms included the suppression of p38 MAPK activation and mitochondrial stress pathways.
肾缺血再灌注损伤（RIRI）是指长时间缺血后血液灌注恢复时肾功能的不可逆损伤，在临床手术中很常见，被认为是急性肾衰竭（ARF）的主要风险因素，伴随着难以想象的高发病率和死亡率。缺血期间的缺氧，随后通过再灌注进行再氧合，是导致细胞凋亡的主要事件，这已被广泛认为是 RIRI 的重要发病机制。防止肾小管上皮细胞凋亡被认为是阻断 RIRI 的有效方法。在本文中，我们在人近端肾小管上皮细胞 HK-2 细胞中建立了缺氧/复氧（H/R）损伤模型。在这里，我们发现 H/R 损伤的 HK-2 细胞中 SPHK1 水平升高，贝母碱处理后可显著下调。贝母碱已被报道对 H/R 诱导的 HK-2 细胞凋亡具有保护作用。因此，在本研究中，我们计划研究 SPHK1 是否参与贝母碱在 H/R 损伤的 HK-2 细胞中的抗凋亡过程。我们的研究通过促进细胞活力、抑制细胞凋亡以及下调 p-P38、caspase-3、caspase-9 和 SPHK1，同时上调 Bcl-2/Bax 的比值，证实了贝母碱对 HK-2 细胞中 H/R 诱导的凋亡的保护作用。然而，HK-2 细胞中 SPHK1 的过表达诱导严重的细胞凋亡，贝母碱处理可显著改善这种情况。我们得出结论，贝母碱通过下调 SPHK1 表达水平，显著防止 HK-2 细胞发生 H/R 诱导的凋亡，其机制包括抑制 p38 MAPK 激活和线粒体应激途径。
