Volume 86, Issue 4, Pages 693-700 (October 2014) Sodium–glucose linked transporter-2 inhibitors: potential for renoprotection beyond blood glucose lowering?  Richard E. Gilbert  Kidney International  Volume 86, Issue 4, Pages 693-700 (October 2014) DOI: 10.1038/ki.2013.451 Copyright © 2014 International Society of Nephrology Terms and Conditions

Figure 1 Diagram showing the relationship between Na+/glucose reabsorption and single-nephron glomerular filtration rate (SNGFR) in diabetes with and without sodium–glucose linked cotransporter-2 (SGLT2) inhibition. (a) Diabetes. (1) Increased glucose in the glomerular ultrafiltrate leads to augmented glucose delivery to the proximal tubule. (2) As SGLT1 and 2 co-transport Na+ with glucose, Na+ delivery to the macula densa ([Na,Cl,K]MD) will be diminished. (3) This reduces the tubuloglomerular feedback (TGF) signal thereby increasing SNGFR. (b) Diabetes+SGLT2 inhibition. (1) By reducing glucose reabsorption, SGLT2 inhibition also reduces Na+ reabsorption in the proximal tubule. (2) Na+ delivery to the macula densa will therefore be increased, augmenting the TGF signal, and (3) reducing SNGFR. Adapted from Vallon.71 Kidney International 2014 86, 693-700DOI: (10.1038/ki.2013.451) Copyright © 2014 International Society of Nephrology Terms and Conditions

Figure 2 Changes in GRF. (a) Changes in estimated glomerular filtration rate (eGFR) over time in type 2 diabetic subjects with moderate renal impairment (baseline eGFR ≥30 and <50ml/min per 1.73m2) treated with placebo, canagliflozin 100mg and 300mg. (b) Changes in eGFR over time in type 2 diabetic subjects with moderate renal impairment (baseline eGFR ≥30 and <60ml/min per 1.73m2) treated with placebo, dapagliflozin 5mg and 10mg. CANA, canagliflozin; LS, least squares. Adapted from Yale et al.24, Adapted from Kohan et al.25 Kidney International 2014 86, 693-700DOI: (10.1038/ki.2013.451) Copyright © 2014 International Society of Nephrology Terms and Conditions

Figure 3 Proportion of participants in canagliflozin (CANA) cardiovascular safety study of subjects with type 2 diabetes experiencing a ≥1-step progression in albuminuria stage.26 Kidney International 2014 86, 693-700DOI: (10.1038/ki.2013.451) Copyright © 2014 International Society of Nephrology Terms and Conditions

Figure 4 Response of renal proximal tubular cell line to glucose in vitro. (a) Following 72h of growth arrest, 25mmol/l glucose was added to the apical compartment of proximal tubular cells, while 5mmol/l glucose was added to the basolateral compartment. Intracellular glucose (bar graph columns) was measured after lysing cells in ice cold sterile water, showing rapid (1h) elevation in intracellular glucose. Apical supernatant glucose concentration (red) fell with time, while the basolateral glucose concentration (blue) rose, consistent with glucose transport from the apical aspect, through the cell and into the basolateral (interstitial) compartment. (b) In response to high glucose (25mmol/l) exposure on their apical aspect, proximal tubular epithelial cells secrete fibronectin basolaterally where it can accumulate to cause peritubular basement membrane thickening and ultimately interstitial fibrosis. By contrast, 25mmol/l L-glucose, the non-metabolizable stereoisomer of biological D-glucose, was without effect, as was the non-metabolizable, alpha-methyl-glucose. *P<0.05. Adapted from Morrisey et al.65, Adapted from Morrisey et al.65 Kidney International 2014 86, 693-700DOI: (10.1038/ki.2013.451) Copyright © 2014 International Society of Nephrology Terms and Conditions