Effects of SGLT2 Inhibitor and Dietary NaCl on Glomerular Hemodynamics Assessed by Micropuncture 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 glomerular capillary pressure (PGC) via a tubuloglomerular feedback (TGF) response to a decrease in proximal reabsorption (Jprox). However, the effect of SGLT2 inhibition on PGC has not been measured. We studied effects of acute SGLT2 blockade (ertugliflozin) on Jprox and glomerular hemodynamics in 2-period micropuncture experiments using STZ-diabetic rats fed high or low NaCl diets (HS/LS). PGC was measured by direct capillary puncture or computed from tubular stop-flow pressure (PSF). TGF is intact while measuring PGC directly, but rendered inoperative when measuring PSF. Results: Acute SGLT2 inhibitor reduced Jprox by ~ 30%, reduced PGC by 5-8 mmHg and reduced GFR by ~25% (all P<0.0001) but had no effect on PSF. The decrease in PGC was larger in LS (8 vs 5 mmHg, P=0.04) where PGC was higher to begin with (54 vs 50 mmHg, P=0.003). Greater decreases in PGC corresponded, unexpectedly, to lesser decreases in GFR (P=0.04). Conclusion: These studies confirm expectations that PGC would decline in response to acute SGLT2 inhibition and that a functioning TGF system is required for this. We infer a contribution of post-glomerular vasorelaxation to the TGF responses where decreases in PGC were large and decrease in GFR were small.