Knockout of Na-glucose-cotransporter SGLT1 mitigates diabetes-induced upregulation of nitric oxide synthase-1 in macula densa and glomerular hyperfiltration.

Knockout of Na-glucose-cotransporter SGLT1 mitigates diabetes-induced upregulation of nitric oxide synthase-1 in macula densa and glomerular hyperfiltration. Am J Physiol Renal Physiol. 2019 May 15;: Authors: Song P, Huang W, Onishi A, Patel R, Kim YC, van Ginkel C, Fu Y, Freeman B, Koepsell H, Thomson SC, Liu R, Vallon V Abstract The Na-glucose-cotransporter SGLT1 mediates glucose reabsorption in late proximal tubules. SGLT1 also mediates macula densa-sensing of an increase in luminal glucose, which increases nitric oxide synthase-1 (MD-NOS1)-mediated NO formation and potentially GFR. Here the contribution of SGLT1 was tested by gene-knockout (-/-) in type 1 diabetic Akita mice. A low-glucose diet was fed to prevent intestinal malabsorption in Sglt1-/- mice and minimize the contribution of intestinal SGLT1. Hyperglycemia was modestly reduced in Sglt1-/- vs littermate wild-type (WT) Akita mice (480 vs. 550mg/dl), associated with reduced diabetes-induced increases in GFR, kidney weight, glomerular size, and albuminuria. Blunted hyperfiltration was confirmed in streptozotocin-induced diabetic Sglt1-/- mice, associated with similar hyperglycemia vs WT mice (350 vs. 385mg/dl). Absence of SGLT1 attenuated upregulation of MD-NOS1 protein expression in diabetic Akita mice and in response to SGLT2 inhibition in non-diabetic mice. During SGLT2 inhibition in Akita mice, Sglt1-/- likewise reduced blood glucose (200 vs. 300mg/dl), associated wit...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research