Glucagon like peptide-1 modulates urinary sodium excretion in diabetic kidney disease via ENaC activation

Diabetic kidney disease (DKD) is a leading cause of end stage kidney disease. Elevated salt sensitivity by epithelial sodium channel (ENaC) overexpression may be a residual risk factor for DKD. We found that combination therapy of linagliptin (LINA) to empagliflozin (EMPA), but not EMPA alone decreased phosphorylated Nedd4-2 (p-Nedd4-2) and ENaC levels in DKD rats in association with the increased urinary sodium excretion (USE). More extensive renoprotective effects were observed by the combination therapy of LINA and EMPA in deoxycorticosterone and high salt-treated mice. Acute injection experiments showed time-lagged administration of LINA to EMPA increased USE, and its effect sustained until 3 h. High salt and high glucose increased p-Nedd4-2 and ENaC levels in cultured distal tubules, which was inhibited by LINA or glucagon like peptide-1 (GLP-1), but there were no additive effects of LINA on GLP-1, the latter of which was blocked by GLP-1 receptor agonist. USE was higher and ENaC expression was lower in DKD patients received SGLT2is and DPP4is than those without. Our present findings suggest that addition of LINA to EMPA decreases p-Nedd4-2 and ENaC levels via the activation of GLP-1-receptor axis, which could ameliorate salt sensitivity and help prevent kidney injury in DKD.