An SGLT2 inhibitor, canagliflozin, reduces blood glucose level in the renal capillaries and protects the capillary network in the diabetic rats

AbstractAimSodium‐glucose cotransporter 2 (SGLT2) inhibitors consistently demonstrate renal protection against progressive kidney disease. We hypothesised that SGLT2 inhibition reduces blood glucose levels in peri‐proximal tubular capillaries by limiting reabsorption from the tubular filtrate, thereby safeguarding the renal microvasculature from hyperglycaemic stress.Materials and MethodsIn anaesthetised streptozotocin‐induced type 1 and Otsuka‐Long Evans fatty (OLETF) type 2 diabetic rats, we measured the arterial‐to‐renal venous glucose ratio (RV/A) to evaluate the effects of canagliflozin, a SGLT2 inhibitor.ResultsIn fasting OLETF rats, three‐day oral canagliflozin treatment at both glycaemic and subglycaemic doses significantly lowered the RV/A glucose ratio compared with vehicle. During anaesthesia, duodenal glucose infusion increased the RV/A glucose ratio in diabetic OLETF rats, an effect prevented by canagliflozin but not by acute insulin infusion. Moreover, 4‐week canagliflozin therapy preserved renal capillary density more effectively than insulin in OLETF rats.ConclusionThese findings indicate that canagliflozin offers superior protection of the renal microvasculature from hyperglycaemic stress, independent of its systemic glucose‐lowering action.