Sodium-Dependent Glucose Transporter-2 Inhibitor Enhances the Hypotensive Effect of Renal Denervation by Inhibiting Sympathetic Activity and Inflammatory Reaction.

Abstract

Background: Sodium-dependent glucose transporter-2 inhibitors (SGLT-2i) have potential hypotensive effects, enhancing the hypotensive effect of renal denervation (RDN). Spontaneously hypertensive rats (SHRs) were used to verify this hypothesis and explore the associated underlying pathways.

Methods: Seven Wistar-Kyoto (WKY) rats and 35 SHRs were divided into 6 groups. The blank WKY control (W) group consisted of all 7 WKY rats, whereas the SHRs were divided into the following groups, each containing 7 rats: sham operation (Sham), renal denervation (RDN), SGLT-2 inhibitor treatment (SGLT-2i), and the combination of renal denervation with SGLT-2 inhibitor treatment (RDN+SGLT-2i). The rats in the RDN+SGLT-2i and SGLT-2i groups were gavaged with dapagliflozin (DAPA) before RDN. The sham group was subjected to a sham operation. One-week post-operation, rat tail manometry, and echocardiography were subsequently performed, and peripheral blood inflammatory cells were detected via flow cytometry before sample collection. Following sample collection, the serum, including interleukin-6, angiotensin-II, renin, and norepinephrine, was tested via enzyme-linked immunosorbent assay. Pathological testing included Masson staining of the myocardial tissue, tyrosine hydroxylase (TH) immunohistochemistry, and Fos protooncogene (C-Fos) immunofluorescence staining of the hypothalamus tissue.

Results: Compared with RDN alone, RDN following intragastric DAPA administration reduced systolic blood pressure (SBP) in SHRs, independent of its hypoglycemic effect. Compared with the RDN group, the pathological results of the RDN+SGLT-2i group revealed a greater improvement in the intensity of TH staining in the hypothalamus tissue, closer to the normal level of the cross-sectional area in myocardial cells. Furthermore, we observed enhanced sympathetic inhibition in the brain and a reduction in the fibrotic area within myocardial cells. Additionally, the proportions of inflammatory mononuclear cell subsets and the levels of inflammatory factors improved. Although DAPA reduced inflammation and sympathetic nerve overexcitation alone, it could not completely reverse blood pressure (BP) or cardiac function. Similarly, the alleviation of inflammation and BP reduction in RDN-treated rats were inferior to those in rats treated with RDN combined with DAPA.

Conclusions: Compared with RDN alone, DAPA addition before RDN can considerably reduce the BP of SHRs. The enhancement of the hypotensive effect may be attributed to the inhibition of sympathetic activity and the reduction in inflammatory reactions.