Impact of sodium glucose linked cotransporter-2 inhibition on renal microvascular oxygen tension in a rodent model of diabetes mellitus

Background: The mechanisms whereby inhibitors of sodium-glucose linked cotransporter-2 (SGLT2) exert their nephroprotective effects in patients with diabetes are incompletely understood but have been hypothesized to include improved tissue oxygen tension within the renal cortex. The impact of SGLT2 inhibition is likely complex and region specific within the kidney. We hypothesize that SGLT2 inhibitors have differential effects on renal tissue oxygen delivery and consumption in specific regions of the diabetic kidney, including the superficial cortex, containing SGLT2-rich components of proximal tubules, versus the deeper cortex and outer medulla, containing predominantly SGLT1 receptors. Methods: We measured glomerular filtration rate (GFR), microvascular kidney oxygen tension (PkO2), erythropoietin (EPO) mRNA, and reticulocyte count in diabetic rats (streptozotocin) treated with the SGLT2 inhibitor, dapagliflozin. Utilizing phosphorescence quenching by oxygen and an intravascular oxygen sensitive probe (Oxyphor PdG4); we explored the effects of SGLT2 inhibition on PkO2 in a region-specific manner, in vivo, in diabetic and non-diabetic rats. Superficial renal cortical or deeper cortical and outer medullary PkO2 were measured utilizing excitations with blue and red light wavelengths, respectively. Results: In diabetic rats treated with dapagliflozin, measurement within the superficial cortex (blue light) demonstrated no change in PkO2. By contrast, measurements in the deeper cortex and outer medulla (red light) demonstrated a significant reduction in PkO2 in dapagliflozin treated diabetic rats (p = 0.014). Consistent with these findings, GFR was decreased, hypoxia-responsive EPO mRNA levels were elevated and reticulocyte counts were increased with SGLT2 inhibition in diabetic rats (p < 0.05 for all). Conclusions: These findings indicate that microvascular kidney oxygen tension is maintained in the superficial cortex but reduced in deeper cortical and outer medullary tissue, possibly due to the regional impact of SGLT-2 inhibition on tissue metabolism. This reduction in deeper PkO2 had biological impact as demonstrated by increased renal EPO mRNA levels and circulating reticulocyte count.