Metformin Normalises Medullary Hypoxia in The Diabetic Rat Kidney

Abstract

BackgroundMetformin is the first choice treatment of type‐2 diabetes where it can lower the level of blood glucose by inhibiting hepatic gluconeogenesis and increase cellular glucose uptake. Besides the effect on blood glucose metformin has also shown protective effects in several renal diseases including diabetic nephropathy. The development of hypoxia in the kidney is suggested to be an important driving force for the development of diabetic nephropathy and we therefore wanted to investigate how metformin affects the oxygenation levels and mitochondrial function in the diabetic kidney.MethodsSprague Dawley rats were injected with streptozotocin (STZ) (50 mg/kg) and when rats were diabetic, metformin (250 mg/kg) was administrated in the drinking water. Rats were prepared for In Vivo measurements 25–30 days after STZ injection. Rats were anesthetized, placed on a heating pad, tracheotomized and a catheter was placed in the left femoral vein for infusion of Ringer solution containing H‐inulin and Para‐aminohippurate. The left femoral artery was catheterized for blood pressure measurements and blood sampling. The left kidney was exposed by a subcostal flank incision, immobilized in a plastic cup and catheters were placed in the left ureter as well as bladder for collection of urine. Intrarenal pO2 was measured in kidney cortex and medulla by oxygen microsensors. To assess mitochondrial function, mitochondria were isolated from kidney cortex and medulla and analyzed by high‐resolution respirometry (Oroboros, O2‐K)Important findingsDiabetic rats showed increased glomerular filtration rate (GFR), which was not affected by metformin treatment. PO2 was lower both in the outer medulla as well as cortex in the diabetic animals. Metformin treatment elevated PO2 in the outer medulla both in the control animals as well as in the diabetic animals. Isolated mitochondria from the outer medulla of diabetic rats showed a significantly higher GDP dependent respiration which was normalized by metformin treatment indicating inhibition of uncoupling protein 2 (UCP2) activity.ConclusionMetformin increases PO2 in the outer medulla both in control and diabetic animals, this could in part be mediated by inhibition of UCP2.