Renal Effects of SGLT2 Inhibitors: An Update

Josselin Nespoux; Volker Vallon


Curr Opin Nephrol Hypertens. 2020;29(2):190-198. 

In This Article

Extending the Tubular Hypothesis of Diabetic Hyperfiltration to a new Role of SGLT1 in the Macula Densa: Implications for SGLT2 Inhibition

Recent studies identified the SGLT1-nitric oxide synthase 1 (NOS1) axis in macula densa cells as a new contributor to glomerular hyperfiltration in diabetes. Zhang et al. demonstrated SGLT1 expression at the luminal membrane of macula densa cells in humans and found that acute hyperglycemia in mice increases GFR by a mechanisms that involve NOS1 in the macula densa.[53] Moreover, studies in isolated perfused juxtamedullary nephrons and micropuncture studies revealed that increased tubular glucose blunts the TGF response, and that this effect is mediated by SGLT1, which senses luminal glucose and enhances MD NOS1 protein expression and phosphorylation, resulting in increased NO production thereby attenuating the vasoconstrictor effect of TGF[53] (Figure 3). Moreover, Song et al.[25] demonstrated that the concept is relevant in T1DM Akita and STZ-diabetic mice, inasmuch as glomerular hyperfiltration is attenuated in mice lacking SGLT1 with minimal or no effects on blood glucose levels. Moreover, absence of SGLT1 prevents the increase in MD NOS1 expression observed in T1DM Akita mice or in response to an SGLT2 inhibitor in nondiabetic mice. Notably, SGLT2 inhibition in T1DM Akita mice lowers MD NOS1 expression. This is consistent with the notion that multiple factors regulate MD NOS1 (Figure 3). The authors speculated that the natriuretic and diuretic effect of the SGLT2 inhibitor reduces effective circulating volume,[54] a stimulator of MD NOS1, thereby opposing any macula densa glucose effect and causing a net reduction (Figure 3). This net response was likely facilitated by the fact that in more severe conditions of hyperglycemia, chronic SGLT2 inhibition is not expected to change MD glucose because of the associated reduction in GFR and blood glucose.[25] Nevertheless, this new MD SGLT1 NOS1 mechanism may play a role in patients who show a blunted GFR-lowering effect in response to initiating SGLT2 inhibition.