顺铂已被广泛研究并发现是一种高效的抗肿瘤药物。它有几个副作用,包括急性肾损伤(AKI)。顺铂诱导的AKI可主要归因于氧化应激,炎症,和凋亡。CTRP3脂肪因子是一种新的脂肪因子,表现出抗氧化剂,抗炎,和抗凋亡特性。尽管如此,CTRP3在AKI中的作用尚不清楚.在顺铂诱导的AKI模型中,我们的研究结果表明,CTRP3在人近端小管上皮细胞(HK-2)中的表达降低。在体外实验中,首先用CTRP3的过表达质粒(pcDNA-CTRP3)或CTRP3的小干扰RNA(si-CTRP3)转染HK-2细胞,并由顺铂诱导;和细胞氧化应激,炎症,扩散,并且发现存在细胞凋亡。过表达CTRP3通过降低丙二醛(MDA)水平和增加SOD和CAT活性来抑制氧化应激。响应于CTRP3过表达,SOD1和SOD2的mRNA水平增加。此外,CTRP3降低TNF-α和MCP-1水平。此外,CTRP3过表达增加顺铂诱导的细胞活性,减少细胞凋亡,如EdU阳性细胞数量增加和凋亡细胞数量减少所示。与这些结果一致,CTRP3的过表达有效地提高了Bcl-2的mRNA水平,降低了Bax的mRNA水平。相比之下,si-CTRP3对CTRP3表达的抑制逆转了顺铂诱导的指标。机械上,我们发现CTRP3的过表达可以增加Nrf2的表达并抑制MAPK磷酸化的激活(ERK,JNK,andp38).此外,ERK的抑制,JNK和p38活性消除了CTRP3敲低引起的顺铂诱导的炎症和凋亡的加重。此外,顺铂诱导的氧化应激和MAPK磷酸化激活(ERK,JNK,和p38)在HK-2细胞中通过siRNA抑制Nrf2逆转。总的来说,这些结果表明,CTRP3可能成为AKI治疗的新靶点,并通过Nrf2/MAPK通路对抗顺铂诱导的AKI.
Cisplatin has been widely studied and found to be a highly effective anti-tumor drug. It has several side effects, including acute kidney injury (AKI). Cisplatin-induced AKI can be primarily attributed to oxidative stress, inflammation, and apoptosis. The CTRP3 adipokine is a new adipokine that exhibits antioxidant, anti-inflammatory, and antiapoptotic properties. Despite this, the role of
CTRP3 in AKI remain unclear. In cisplatin-induced AKI models, our findings demonstrated that CTRP3 expression was decreased in human proximal tubule epithelial cells (HK-2). In the in vitro experiments, HK-2 cells were first transfected with an overexpression plasmid of CTRP3 (pcDNA-
CTRP3) or a small interfering RNA for
CTRP3 (si-
CTRP3) and induced by cisplatin; and cell oxidative stress, inflammation, proliferation, and apoptosis were found to be present. Overexpressing CTRP3 inhibited oxidative stress through decreasing malondialdehyde (MDA) levels and increasing the activity of SOD and CAT. The mRNA levels of SOD1 and SOD2 were increased in response to
CTRP3 overexpression. Additionally,
CTRP3 decreased TNF-α and MCP-1 levels. Moreover, CTRP3 overexpression increased cisplatin-induced cell activity and decreased cell apoptosis, as indicated by the elevated numbers of EdU positive cells and decreased numbers of apoptotic cells. Consistent with these results, the overexpression of CTRP3 effectively elevated the mRNA levels of Bcl-2 and reduced the mRNA levels of Bax. In contrast, inhibition of
CTRP3 expression by si-
CTRP3 reversed the cisplatin-induced indices. Mechanistically, we found that the overexpression of CTRP3 can increase expression of Nrf2 and inhibit the activation of MAPK phosphorylation (ERK, JNK, and p38). Furthermore, inhibition of ERK, JNK and p38 activity eliminated aggravation of cisplatin-induced inflammation and apoptosis caused by CTRP3 knockdown. Additionally, the cisplatin-induced oxidative stress and activation of MAPK phosphorylation (ERK, JNK, and p38) in HK-2 cells were reversed by Nrf2 suppression by siRNA. Collectively, these results indicated that CTRP3 may identify as a novel target for AKI treatment and protect against cisplatin-induced AKI through the Nrf2/MAPK pathway.