RNA-Seq transcriptomic landscape profiling of spontaneously hypertensive rats treated with a sodium-glucose cotransporter 2 (SGLT2) inhibitor

作者全名："Tan, Fangyan; Long, Xianglin; Du, Jianlin; Yuan, Xin"

作者地址："[Tan, Fangyan; Yuan, Xin] Chongqing Med Univ, Affiliated Hosp 2, Dept Nephrol, Chongqing 400010, Peoples R China; [Long, Xianglin; Du, Jianlin] Chongqing Med Univ, Affiliated Hosp 2, Dept Cardiol, Chongqing 400040, Peoples R China"

通信作者："Yuan, X (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Nephrol, Chongqing 400010, Peoples R China."

来源：BIOMEDICINE & PHARMACOTHERAPY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001062196200001

JCR分区：Q1

影响因子：7.5

年份：2023

卷号：166

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：SGLT-2 inhibitors; Empagliflozin; RNA-Seq; Hypertension; Kidney

摘要："Background: 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.Methods: 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.Results: 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.Conclusions: 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."

基金机构：National Natural Science Foundation of China (NSFC) [81900631]; China Postdoctoral Science Foundation [2019M653354]

基金资助正文："This work was funded by grants from the National Natural Science Foundation of China (NSFC, 81900631), China Postdoctoral Science Foundation (2019M653354). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."