Streptozotocin induces renal proximal tubular injury through p53 signaling activation. Streptozotocin induces renal proximal tubular injury through p53 signaling activation

Streptozotocin (STZ) is an anti-cancer drug that is primarily used to treat neuroendocrine tumors (NETs) in clinical settings and develop type 1 diabetes rodent models in experimental fields. STZ is incorporated into cells through the glucose transporter, GLUT2, which is primarily expressed in pancreatic β-cells or proximal tubular epithelial cells in the kidney. However, its cytotoxic effects on kidney cells have been underestimated and the underlying mechanisms remain unclear. We herein demonstrated that DNA damage and subsequent p53 signaling were responsible for the development of STZ-induced tubular epithelial injury. We detected tubular epithelial DNA damage in NET patients treated with STZ. Unbiased transcriptomics of tubular epithelial cells in vitro showed the activation of the p53 signaling pathway by STZ. STZ induced DNA damage and activated p53 signaling in vivo in a dose-dependent manner, resulting in reduced membrane transport. The localization of STZ-induced kidney injury was limited to within the kidney cortex, which was independent of blood glucose. The pharmacological inhibition of p53 and sodium-glucose transporter 2 (SGLT2) mitigated STZ-induced epithelial injury. However, the cytotoxic effects of STZ on pancreatic β-cells were preserved in SGLT2 inhibitor-treated mice. The present results demonstrate the strong proximal tubular-specific cytotoxicity of STZ and the underlying mechanisms in vivo, which may be ameliorated by a SGLT2 inhibitor pretreatment. Since the cytotoxic effects of STZ against β-cells were not impaired by dapagliflozin, a pretreatment with a SGLT2 inhibitor has potential as a preventative remedy for kidney injury in NET patients treated with STZ. Overall design: Comparative gene expression profiling analysis of RNA-seq data for control NRK-52E cells and STZ-treated NRK-52E cells.

链脲佐菌素（Streptozotocin，STZ）是一款抗癌药物，临床主要用于治疗神经内分泌肿瘤（neuroendocrine tumors，NETs），实验领域则多用于构建1型糖尿病啮齿类动物模型。STZ可通过葡萄糖转运蛋白（GLUT2）进入细胞，该蛋白主要在胰腺β细胞或肾脏近端小管上皮细胞中表达。然而，其对肾脏细胞的细胞毒性作用长期被低估，且具体分子机制尚未阐明。本研究证实，DNA损伤及后续激活的p53信号通路是STZ诱导肾小管上皮损伤的核心机制。我们在接受STZ治疗的NET患者体内检测到了肾小管上皮DNA损伤。体外实验中对肾小管上皮细胞的无偏倚转录组学分析显示，STZ可激活p53信号通路。体内实验表明，STZ可通过剂量依赖性方式诱导DNA损伤并激活p53信号通路，最终导致膜转运功能受损。STZ诱导的肾损伤定位局限于肾皮质，且该过程不依赖血糖水平。对p53及钠-葡萄糖协同转运蛋白2（SGLT2）进行药物抑制，可减轻STZ诱导的上皮损伤。但在接受SGLT2抑制剂治疗的小鼠中，STZ对胰腺β细胞的细胞毒性作用并未受到影响。本研究结果明确了STZ对肾脏近端小管的特异性强细胞毒性及其体内作用机制，该损伤可通过SGLT2抑制剂预处理得到改善。由于达格列净（dapagliflozin）并不会削弱STZ对β细胞的细胞毒性，因此SGLT2抑制剂预处理有望成为预防接受STZ治疗的NET患者肾损伤的潜在方案。实验整体设计：对对照组NRK-52E细胞与STZ处理组NRK-52E细胞的RNA测序（RNA-seq）数据进行对比基因表达谱分析。