SGLT2 inhibitors are the new mainstay of diabetes mellitus and cardiovascular diseases treatment. Despite the remarkable benefits, the molecular mechanisms mediating the effects of SGLT2 inhibitors on water and electrolyte balance are incompletely understood. The goal of this study was to determine whether SGLT2 inhibition alters blood pressure and kidney function via affecting the Renin-Angiotensin-Aldosterone System (RAAS) and sodium channels/transporters along the nephron in Dahl Salt-Sensitive (SS) rats, a model of salt-induced hypertension. Administration of dapagliflozin (Dapa) at 2 mg/kg/day via drinking water for 3 weeks blunted the development of salt-induced hypertension as evidenced by lower blood pressure and a left shift of the pressure natriuresis curve. Urinary flow rate, glucose excretion, and Na+ and Cl-/creatinine ratios increased in Dapa-treated compared to vehicle-treated rats. To define the contribution of RAAS, we measured various hormones. Despite apparent effects on Na+ and Cl-/creatinine ratios, Dapa treatment did not affect RAAS metabolites. Subsequently, we assessed the effects of Dapa on renal Na+ channels and transporters using RT-PCR, Western blotting, and patch-clamp. Neither mRNA nor protein expression levels of tested renal transporters (SGLT2, NHE3, NKCC2, NCC, and α-, β-, γ- ENaC subunits) changed significantly between groups. Furthermore, electrophysiological studies did not reveal any difference in Dapa treatment on the conductance and activity of ENaC. Our data suggest that SGLT2 inhibition in a non-diabetic model of salt-sensitive hypertension blunts the development of salt-induced hypertension by causing glucosuria and natriuresis without changes in RAAS and expression or activity of studied Na+ channels and transporters.

Cannabinoids and their endogenous and synthetic analogs impact blood pressure and contribute to the incidence of hypertension. It was previously reported that the endocannabinoid system plays an important role in developing hypertension; however, it was also shown that cannabinoids elicit profound hypotension associated with hemorrhagic, cardiogenic, and endotoxic shock. This study aimed to test acute and chronic effects of an endogenous ligand of cannabinoid receptor anandamide (AEA) on blood pressure and kidney injury in vivo in conscious Dahl salt-sensitive (SS) rats. We demonstrated that acute i.v. bolus administration of a low or a high doses (0.05 or 3 mg/kg) of AEA did not affect blood pressure for 2 h after the injection in Dahl SS rats fed a normal salt diet (0.4% NaCl). Neither low nor high doses of AEA had any beneficial effects on blood pressure or kidney function. Furthermore, hypertensive rats fed a HS diet (8% NaCl) and chronically treated with 3 mg/kg of AEA exhibited a significant increase in blood pressure accompanied by increased renal interstitial fibrosis and glomerular damage at the late stage of hypertension. Western blot analyses revealed increased expression of Smad3 protein levels in the kidney cortex in response to chronic treatment with a high AEA dose. Therefore, TGF-β1/Smad3 signaling pathway may play a crucial role in kidney injury in SS hypertension during chronic treatment with AEA. Collectively, these data indicate that prolonged stimulation of cannabinoid receptors may result in aggravation of hypertension and kidney damage.

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