Sodium–glucose cotransporter 2 (SGLT2) is thought to have a role in the pathogenesis of glomerular hyperfiltration in diabetes mellitus. A recent study by Jie Zhang and colleagues reports a novel mechanism by which SGLT1 might also contribute to the control of tubuloglomerular feedback (TGF) and glomerular filtration rate (GFR) in the setting of hyperglycaemia.

The researchers report that intravenous injection of glucose induced hyperglycaemia and significantly increased GFR in nondiabetic mice. Using microperfusion and micropuncture techniques, they show that tubular glucose inhibits the TGF response in vitro and in vivo and stimulates the generation of nitric oxide (NO) at the macula densa. As these effects were blocked by an SGLT1 inhibitor and further analyses indicated that SGLT1 is expressed in macula densa cells, the researchers suggest that tubular glucose inhibits TGF and stimulates NO generation via SGLT1.

Zhang and colleagues also show that glucose upregulates the expression and phosphorylation of nitric oxide synthase 1 (NOS1) in human and mouse renal cortex. Selective knockout of NOS1 in macula densa cells abrogated glucose-induced NO generation, inhibition of the TGF response and hyperfiltration in nondiabetic mice.

“We assume that hyperglycaemia increases glucose filtration and enhances SGLT2-mediated sodium–glucose reabsorption, which decreases NaCl delivery to the macula densa and inhibits the vasoconstrictor TGF tone,” comments Zhang. “Our study suggests that increased luminal glucose at the macula densa is also sensed by SGLT1, which upregulates NOS1 expression and activity and further reduces vasoconstrictor TGF tone. Thus, these two signalling pathways additively promote glomerular hyperfiltration in diabetes.”