Elucidation of the Renoprotective Effects of SGLT2 Inhibitors in Nondiabetic CKD

Background: In the DAPA-CKD trial, dapagliflozin, an inhibitor of Sodium Glucose Cotransporter 2 (SGLT2), has shown the renoprotective effects in patients with chronic kidney disease (CKD), regardless of type 2 diabetes status. Previously, we demonstrated that the involvement of the tubuloglomerular glomerular feedback (TGF) mechanism mediated by the adenosine/adenosine A1 receptor pathway in the pathogenesis of glomerular hyperfiltration in type 1 diabetic mice (Circulation 2019), and observed that SGLT2 inhibition alleviated glomerular hyperfiltration in those mice. However, the renoprotective mechanisms of SGLT2 inhibitor in non-diabetic CKD remain unclear. The aim of this study is to verify the contribution of SGLT2 as an important factor in compensatory glomerular filtration, throughing mechanisms such as increased glucose load to the remnant nephrons due to a decrease in the number of nephrons, enhanced Na+ reabsorption through SGLT2 and reduced Na+ delivery to the macula densa. Methods: Male C57BL/6 mice were subjected to infarction-inducing 5/6 nephrectomy (Nx) to establish a CKD model. The experimental groups comprised a control group, a 5/6Nx group, and a 5/6Nx group treated with an SGLT2 inhibitor for one week. Single Nephron Glomerular Filtration Rate (SNGFR) was measured using in vivo imaging techniques. Additionally, Proximal tubular reabsorption of 2-NDBG (2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl) amino]-D-glucose) injected transarterially via catheter was also evaluated in vivo. The urinary excretion of adenosine, which is a vasoconstrictive factor of TGF, was quantified. Results: SNGFR was significantly increased in 5/6Nx group compared to the control group. Additionally, the 5/6Nx group exhibited increase in the uptake of 2-NBDG relative to the control group, whereas the group receiving SGLT2 inhibitor treatment displayed reduction in uptake. Moreover, the SGLT2 inhibitor treatment group exhibited augmentation in the urinary excretion of adenosine in comparison to the 5/6Nx group. Adenosine A1 receptor antagonist administration cancelled the inhibitory effect of SGLT2 inhibitors on hyperfiltration. Conclusion: Increased glucose uptake via SGLT in the proximal tubule initiates the TGF that leads to hyperfiltration of residual nephrons in non-diabetic CKD.