Tan Fangyan, Long Xianglin, Du Jianlin, Yuan Xin
Department of Nephrology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 4000l0, China.
Department of Cardiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400040, China.
Biomed Pharmacother. 2023 Oct;166:115289. doi: 10.1016/j.biopha.2023.115289. Epub 2023 Aug 10.
Sodium-glucose co-transporter-2 inhibitor (SGLT2i) are antihyperglycemic medications that reduce cardiovascular disease (CVD) and improve chronic kidney disease prognosis in patients with diabetes mellitus. The specific impact of SGLT2i treatment on hypertensive individuals, however, remains to be established. This underscores the need for systematic efforts to profile the molecular landscape associated with SGLT2i administration.
We conducted a detailed RNA-sequencing (RNA-Seq)-based exploration of transcriptomic changes in response to empagliflozin in eight different tissues (i.e., atrium, aorta, ventricle, white adipose, brown adipose, kidney, lung, and brain) from a male rat model of spontaneously hypertension. Corresponding computational analyses (i.e., clustering, differentially-expressed genes [DEG], and functional association) were performed to analyze these data. Blood pressure measurements, tissue staining studies and RT-qPCR were performed to validate our in silico findings.
We discovered that empagliflozin exerted potent transcriptomic effects on various tissues, most notably the kidney, white adipose, and lung in spontaneously hypertension rats (SHR). The functional enrichment of DEGs indicated that empagliflozin may regulate blood pressure, blood glucose and lipid homeostasis in SHR. Consistent with our RNA-Seq findings, immunohistochemistry and qPCR analyses revealed decreased renal expression of mitogen-activated protein kinase 10 (MAPK10) and decreased pulmonary expression of the proinflammatory factors Legumain and cathepsin S (CTSS) at 1 month of empagliflozin administration. Notably, immunofluorescence experiments showed increased expression of the AMP-activated protein kinases Prkaa1 and Prkaa2 in white adipose tissue of SHR following empagliflozin therapy. Furthermore, the transcriptomic signatures of the blood pressure-lowing effect by empagliflozin were experimentally validated in SHR.
This study provided an important resource of the effects of empagliflozin on various tissues of SHRs. We identified tissue-specific and tissue-enriched transcriptomic signatures, and uncovered the beneficial effects of empagliflozin on hypertension, weight gain and inflammatory response in validated experiments.
钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）是一类抗高血糖药物，可降低心血管疾病（CVD）风险并改善糖尿病患者的慢性肾病预后。然而，SGLT2i治疗对高血压患者的具体影响仍有待确定。这凸显了系统研究与SGLT2i给药相关分子图谱的必要性。
我们基于RNA测序（RNA-Seq）对自发性高血压雄性大鼠模型的八个不同组织（即心房、主动脉、心室、白色脂肪、棕色脂肪、肾脏、肺和脑）中恩格列净治疗后的转录组变化进行了详细探索。进行了相应的计算分析（即聚类、差异表达基因[DEG]和功能关联分析）以分析这些数据。进行了血压测量、组织染色研究和RT-qPCR以验证我们的计算机模拟结果。
我们发现恩格列净对自发性高血压大鼠（SHR）的各种组织，尤其是肾脏、白色脂肪和肺，具有显著的转录组效应。DEG的功能富集表明恩格列净可能调节SHR的血压、血糖和脂质稳态。与我们的RNA-Seq结果一致，免疫组织化学和qPCR分析显示，在恩格列净给药1个月时，肾脏中丝裂原活化蛋白激酶10（MAPK10）的表达降低，肺中促炎因子Legumain和组织蛋白酶S（CTSS）的表达降低。值得注意的是，免疫荧光实验显示，恩格列净治疗后SHR白色脂肪组织中AMP活化蛋白激酶Prkaa1和Prkaa2的表达增加。此外，在SHR中通过实验验证了恩格列净降低血压作用的转录组特征。
本研究提供了恩格列净对SHR各种组织影响的重要资源。我们确定了组织特异性和组织富集的转录组特征，并在验证实验中揭示了恩格列净对高血压、体重增加和炎症反应的有益作用。
