SET domain with lysine methyltransferase 7/9 (Set7/9), a histone lysine methyltransferase (HMT), recently suggested to exert a critical role among kidney disorders, whereas its role in diabetes associated IRI co-morbidity remains complete elusive. The present study aimed to understand the role of SET7/9 and histone methylation in regulation of inflammatory signaling under IRI in diabetes mellitus and non-diabetic rats. Our results demonstrated that IRI caused renal dysfunction via increased blood urea nitrogen (BUN) levels in ND and DM rats. The NF-κB mediated inflammatory cascade like increased p-NF-κB, reduced IκBα levels followed by enhanced leukocyte infiltration as shown by increased MCP-1 expressions. IRI results in increased histone H3 methylation at lysine 4 and 36 (H3K4Me2, H3K36Me2), and decreased histone H3 methylation at lysine 9. Additionally, IRI increased the protein and mRNA expression of H3K4Me2 specific histone methyltransferase-SET7/9 in DM and ND rats. The abovementioned results remain prominent in DM rats compared to ND rats followed by IRI. Further, treatment with a novel SET7/9 inhibitor; cyproheptadine, significantly improved renal functioning via reducing the BUN levels in ND and DM rats. Hence, this study demonstrated the role of SET7/9 in mediating active transcription via H3K4Me2, ultimately regulated the NFκB-mediated inflammatory cascade. Therefore, SET7/9 can be explored as novel target for drug development against IRI under DM and ND conditions.

中文翻译：

---

SET7 / 9在糖尿病和非糖尿病大鼠缺血性肾损伤进展中的作用。

SET结构域与组蛋白赖氨酸甲基转移酶（HMT）的赖氨酸甲基转移酶7/9（Set7 / 9）最近建议在肾脏疾病中发挥关键作用，而其在糖尿病相关IRI合并症中的作用仍然完全不清楚。本研究旨在了解SET7 / 9和组蛋白甲基化在糖尿病和非糖尿病大鼠IRI下调节炎症信号的作用。我们的研究结果表明，IRI通过增加ND和DM大鼠的血液尿素氮（BUN）水平引起了肾功能不全。NF-κB介导的炎症级联反应，例如p-NF-κB升高，IκBα降低，随后白细胞浸润增强，如MCP-1表达增加所表明。IRI导致赖氨酸4和36（H3K4Me2，H3K36Me2）处的组蛋白H3甲基化增加，而赖氨酸9处的组蛋白H3甲基化降低。另外，IRI增加了DM和ND大鼠中H3K4Me2特异性组蛋白甲基转移酶-SET7 / 9的蛋白质和mRNA表达。与ND大鼠和IRI相比，DM大鼠的上述结果仍然很突出。此外，用新型SET7 / 9抑制剂治疗；赛庚啶通过降低ND和DM大鼠的BUN水平显着改善肾脏功能。因此，这项研究证明了SET7 / 9在通过H3K4Me2介导主动转录中的作用，最终调节了NFκB介导的炎症级联反应。因此，SET7 / 9可以作为在DM和ND条件下针对IRI的药物开发的新靶标进行探索。与ND大鼠和IRI相比，DM大鼠的上述结果仍然很突出。此外，用新型SET7 / 9抑制剂治疗；赛庚啶通过降低ND和DM大鼠的BUN水平显着改善肾脏功能。因此，这项研究证明了SET7 / 9在通过H3K4Me2介导主动转录中的作用，最终调节了NFκB介导的炎症级联反应。因此，SET7 / 9可以作为在DM和ND条件下针对IRI的药物开发的新靶标进行探索。与ND大鼠和IRI相比，DM大鼠的上述结果仍然很突出。此外，用新型SET7 / 9抑制剂治疗；赛庚啶通过降低ND和DM大鼠的BUN水平显着改善肾脏功能。因此，这项研究证明了SET7 / 9在通过H3K4Me2介导主动转录中的作用，最终调节了NFκB介导的炎症级联反应。因此，SET7 / 9可以作为在DM和ND条件下针对IRI的药物开发的新靶标进行探索。