Background: Sodium–glucose cotransporter-2 (SGLT2) inhibitors reduce cardiovascular risk and slow kidney disease progression in patients with diabetes and hypertension. However, the mechanisms underlying their renal function in the context of salt-sensitive hypertension remain unclear. Male Dahl salt-sensitive (SS) rats develop early proteinuria and renal inflammation when challenged with a high-salt (HS) diet. We tested whether SGLT2 inhibition attenuates these early pathological events. Hypothesis: We hypothesized that dapagliflozin (DAPA) would attenuate early renal injury and inflammation during the primary phase of salt-sensitive hypertension. Methods: Male SS rats (n=5-6/ group) were implanted with radiotelemetry transmitters and treated with DAPA (10 mg/kg/day) or vehicle beginning at baseline. After a 3-day control diet (CS, 0.4% NaCl), rats were challenged with a 7-day HS diet (4% NaCl). Mean arterial pressure (MAP) was continuously recorded. 24-hour urine samples were collected for the quantification of proteinuria, and kidneys were harvested for immunohistochemistry and flow cytometry. Statistical analysis was performed using a linear mixed model with Tukey's post hoc test. Results: Over 7-days of HS, MAP was significantly lower in SS rats treated with DAPA than in vehicle controls (Day 7: vehicle: 135 ±4 vs. DAPA: 129±1mmHg, P=0.0132). In contrast, proteinuria was not different between groups (Day 7: vehicle: 77±13 vs. DAPA: 103±23 mg/day, p=0.1138). Using flow cytometry to assess renal inflammation, we found no significant differences between groups in the number of CD11b/c+ monocytes and macrophages (P=0.2370), CD45R+ B-cells (P=0.02370), CD3+ T-cells (P=0.0898), CD4+ T-cells (P=0.0731), and CD8+ T-cells (0.4561). Using immunohistochemistry to evaluate the location of T-cells and macrophages in the kidney, we found no differences in cortical Iba1+ macrophage area (p = 0.4817) or CD3+ T-cell staining (p = 0.5169) between groups, indicating that DAPA did not alter immune cell abundance or renal inflammatory localization. Conclusion: Although DAPA lowers blood pressure during the early phase of salt-sensitive hypertension, it does not mitigate proteinuria or renal inflammation in male SS rats. These findings suggest that early blood pressure lowering effects of SGLT2 inhibition occur independently of reductions in renal inflammation. Funding: Studies funded by R01HL152166 to LE This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Almutlaq et al. (Fri,) studied this question.