Inhibition of SGLT2 reduces blood pressure in the early phase of salt-sensitive hypertension in male Dahl-SS rats independently of changes in renal inflammation.

Salt-sensitive hypertension is a progressive condition characterized by albuminuria, renal injury, and inflammation. The initiating mechanisms remain unclear. We hypothesized that early in salt-sensitive hypertension, the proximal tubule is exposed to excess albumin, thereby triggering cytokine release and renal inflammation. Blood pressure, renal injury, and inflammation were assessed in Dahl salt-sensitive (SS) rats fed a 4.0% NaCl high-salt (HS) diet for 7 days. Using a proximal tubule cell line, we tested whether albumin exposure triggers epithelial cytokine release, and if this is reduced by dapagliflozin. Lastly, we examined whether dapagliflozin modified the response to 7 days HS in SS rats. Urinary albumin and CCL2 were higher in SS rats fed HS than those fed control salt, prior to differences in blood pressure between the groups. After 7 days, renal macrophage accumulation was higher in HS fed SS rats and correlated positively with albuminuria. Albumin induced CCL2 release from cultured proximal tubule cells; this was prevented by dapagliflozin cotreatment. In SS rats, dapagliflozin blunted the development of salt-induced hypertension but didn't reduce renal macrophage accumulation. Albuminuria is a primary event in SS hypertension and is correlated with renal macrophage accumulation. Inhibition of SGLT2 lowers blood pressure but does not reduce renal inflammation.