Effects of Acute SGLT2 Blockade and Dietary NaCl on Glomerular Hemodynamics in Diabetic Rats

Abstract

Inhibitors of the main proximal tubular Na‐glucose cotransporter (SGLT2) mitigate diabetic glomerular hyperfiltration and are approved by FDA for slowing the progression of diabetic kidney disease. It has been proposed that SGLT2 inhibitors improve hard renal outcomes by reducing the glomerular capillary pressure gradient (ΔP) through TGF signaling, which begins with a decrease in fluid reabsorption by the proximal tubule (Jprox). However, the effect of SGLT2 inhibition on ΔP has not been measured up to now.We studied effects of acute SGLT2 blockade (ertugliflozin) on Jprox and glomerular hemodynamics by 2‐period micropuncture in STZ‐diabetic rats fed high or low NaCl diets (HS/LS). ΔP was measured by direct capillary puncture in Wistar Froemter rats (MWF), which have surface glomeruli suitable for this purpose. ΔP was computed from tubular stop‐flow pressure in Wistar rats (Wis), which lack surface glomeruli. Hence, TGF was allowed to operate normally while measuring ΔP in MWF but rendered inoperative while measuring ΔP in Wis. SGLT2 blockade was confirmed to reduce Jprox by collecting fluid from late proximal tubules for volume and inulin clearance.Summary and Conclusions about the diabetic kidney under conditions of moderate hyperglycemia: SGLT2 blockade acutely reduces Jprox, which leads to a decrease in glomerular capillary pressure, but only when TGF is permitted to operate normally. Baseline glomerular capillary pressure varies inversely with dietary NaCl and the impact of SGLT2 blockade applies across a wide range of dietary NaCl.Support or Funding InformationNIDDK RO1 DK112042 Merck Group (n) Glucose (mg/dl) GFR(ml/min) ΔP (mmHg) Jprox' (nl/min) control SGLT2 blocked control SGLT2 blocked control SGLT2 blocked MWF LS (6) 344±41 4.2±0.5 3.5±0.5 * 41.2±1.5 33.0±1.9 * MWF HS (8) 408±35 4.1±0.3 3.3±0.4 * 36.6±1.3 ** 32.4±1.6 * Wis LS (6) 355±41 4.8±0.4 3.8±0.5 * 43.6±1.9 43.7±2.4 18.9±1.3 10.2±1.1 * Wis HS (9) 400±52 4.5±0.5 3.8±0.6 * 32.6±2.3 ** 35.7±3.0 18.1±1.3 12.6±1.1 * *P<0.01 vs control period. **P<0.01 vs LS. Jprox’ is Jprox adjusted for single nephron GFR by ANCOVA to obtain the "primary" effect of SGLT2 blockade on the tubule.