Background: Ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury, usually occurs during renal surgeries, and may eventually lead to chronic kidney diseases. However, effective therapeutic targets for renal I/R injury remain limited. Purpose: In the present study, we investigated whether inhibition of disruptor of telomeric silencing 1-like (Dot1l) could alleviate renal I/R in vivo and in vitro, as well as the potential mechanisms involved in this process. Methods: Sprague-Dawley rats were subjected to right renal ischemia for 45 mins and reperfusion for 0, 7, or 14 days with and without the Dot1l inhibitor EPZ004777. In addition, human renal proximal tubular epithelial cell line human kidney-2 cells were subjected to the hypoxia/reoxygenation (H/R) process (ie, 3 hrs hypoxia, 12 hrs and 24 hrs reoxygenation), with or without Dot1l inhibitor or genetic knockdown. Results: Inhibition of Dot1l through EPZ004777 or genetic knockdown reduced the expression of alpha-smooth muscle actin, vimentin, and fibronectin in I/R-and H/R-induced injury. Moreover, H/R-induced fibrosis depended on oxidative stress in vitro. In addition, I/R-and H/R-induced generation of reactive oxygen species (ROS) was attenuated by EPZ004777 or small interfering RNA for Dot1l. Furthermore, the elevation of ROS induced by Dot1l was regulated via phosphatidylinositol 3-kinase (PI3K) and serine-threonine protein kinase (AKT) phosphorylation in vivo and in vitro. Conclusion: Inhibition of Dot1l alleviated renal fibrosis by preventing the generation of ROS via the PI3K/AKT pathway. These results indicate that inhibitor of Dot1l could be a potential therapeutic target for renal I/R injury.
Targeting programmed cell death protein ligand 1 (PD-L1) remains one of the most essential immunotherapies in cancer1,2. PD-L1 has been detected in the nucleus in multiple malignancies, playing an oncogenic role independent of immune checkpoint regulation3–5. Howbeit, the regulatory function of nuclear PD-L1 (nPD-L1) remains to be fully understood. Here, we report that nPD-L1 is an endogenous accelerator for cancer angiogenesis. First, we found that an abundant proportion of PD-L1 was distributed within the nucleus of uveal melanoma samples, which is associated with an unfavorable outcome. Moreover, the capacity of promoting angiogenesis was largely attenuated in the nPD-L1-deficient cells both in vivo and in vitro. Mechanistically, nPD-L1 facilitates p-STAT3 binding to the promoter of early growth response-1 (EGR1), resulting in the activation of EGR1-mediated angiogenesis. Therapeutically, the inhibition of histone deacetylase 2 restores the normal acetylation level of PD-L1, blocking its nuclear translocation and thereby attenuating tumor angiogenesis. Conclusively, we reveal that nPD-L1 promotes angiogenesis in malignancies, and provide a novel anti-vascularization strategy through blocking aberrant PD-L1 nuclear translocation for tumor therapy.
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