The pressure natriuresis response is not affected by SGLT2 inhibition in rats with Type 1 diabetes mellitus

Increasing blood pressure (BP) induces natriuresis due to downregulation of sodium transport in the proximal tubule. This pressure natriuresis (PN) response regulates BP1. Type-1 diabetic (T1DM) patients show enhanced sodium reabsorption and high BP. In T1DM rats, PN is impaired due to uncoupling of tubular sodium reabsorption from BP2. The molecular mechanism is unknown but the sodium-glucose cotransporter SGLT2 is a plausible candidate and inhibitors induce diuresis in T1DM rats3. This study tested the hypothesis that SGLT2 inhibition with dapagliflozin would improve the acute PN response in T1DM rats. T1DM was induced in male Sprague-Dawley rats by streptozotocin (30-45mg/kg IP; plasma glucose 13.3->35mmol). After 3 weeks rats were anaesthetised with Inactin (120mg/kg, IP). The jugular vein was cannulated and isotonic saline (containing FITC-inulin and p-amino hippurate for measurement of glomerular filtration rate (GFR) and renal plasma flow (RPF)) was infused. Rats were randomly allocated to receive either dapagliflozin (50mg/kg; n=7) or saline vehicle (n=7) and after an equilibration period and baseline urine collection, BP was increased by sequential arterial ligation of first the coeliac and mesenteric arteries and then the distal aorta and the natriuretic response was measured. Experiments were performed under a single blind and rats were euthanised by an overdose of anaesthetic. Data are mean +SD and comparisons were made by 2-way ANOVA. GFR and RPF were not different between treatment groups and were unaffected by the experimentally-induced rise in BP, consistent with autoregulation. In vehicle-treated rats, incremental rises in BP increased urine flow rate from a baseline of 6.2±3.0 to a peak of 51.4±27.7µl/min/gkw (P<0.01), sodium excretion rate from 1.7±0.5 to 16.7±1.4 µmol/min/ gkw (P<0.01) and fractional sodium excretion from 0.2±7.6 to 5.4±4.5% (P<0.01). The dapaglifozin rats responded to increasing pressure with a diuresis and natriuresis but the peak absolute (3.8±4.1µmol/min/gkw; P=0.010) and fractional (15.2±8.0%; P=0.018) sodium excretion were significantly lower than in the vehicle- group. Dapagliflozin increased urinary glucose excretion from 0.1±0.2 to 0.4±0.2µmol/min/gkw. However, although mean BP increased by ~30mmHg in both cohorts, it was lower in dapagliflozin-treated rats by ~14mmHg (P<0.01) and non-linear regression did not separate pressure diuresis (P=0.22) and natriuresis (P=0.53) curves in the two treatment groups. SGLT2 inhibitors induce an increase in urine flow rate and glucose excretion when BP remains at steady state levels, but they do not enhance the acute pressure natriuresis response in anaesthetised T1DM rats. We conclude that impaired pressure natriuresis in T1DM does not reflect increased SGLT2 activity. Ivy JR and Bailey MA. (2014). J Physiol592, 3955-3967 Culshaw GJ et al.(2014). Int Soc Nephrol Intrinsic Renal Regulation Thomson SC et al. (2012). Am J Physiol Regul Integr Comp Physiol 302, R75-R83 British Heart Foundation studentship FS/16/54/32730 & Kidney Research UK Project Grant RP2/2014 Where applicable, the authors confirm that the experiments described here conform with the ethical requirements.