RNA-Seq transcriptome analysis of renal tissue from spontaneously hypertensive rats revealed renal protective effects of dapagliflozin, an inhibitor of sodium-glucose cotransporter 2

Abstract

Hypertensive nephropathy (HTN) is a common complication of hypertension. Although various agents for treatment of hypertension exert significant effects, there is currently no effective treatment for hypertensive nephropathy. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as dapagliflozin (DAPA), are a new class of hypoglycemic agents shown to improve the prognosis of patients with chronic kidney disease and diabetes mellitus. However, the mechanisms underlying the protective effects of DAPA remain unclear. RNA-sequencing (RNA-Seq)-based computational analysis was conducted to explore the transcriptomic changes to spontaneously hypertensive rats (SHRs) treated with DAPA for 8 weeks. Differentially expressed genes in SHRs were related to dysregulation of lipid metabolism, oxidation–reduction reaction, immunity and inflammation in HTN. Transcriptome analysis showed that 8 weeks of DAPA therapy exerted protective effects on the renal tissues of SHRs through the lysosomal, phagosomal, and autophagic pathways. VENN diagram analysis identified Zinc finger and BTB domain-containing 20 (Zbtb20) as the potential target of DAPA therapy. Consistent with the RNA-Seq findings, real-time quantitative PCR and immunohistochemical analyses revealed increased expression of Zbtb20 in the renal tissues of SHRs, whereas expression was decreased following 8 weeks of DAPA administration. The results of this study clarified the transcriptome signature of HTN and the beneficial effects of DAPA on renal tissues by alleviating dysregulation of metabolic processes and reducing inflammation.