Metformin attenuates renal medullary hypoxia in diabetic nephropathy through inhibition uncoupling protein‐2

Abstract

Background The purpose of the study is to examine the effect of metformin on oxygen metabolism and mitochondrial function in the kidney of an animal model of insulinopenic diabetes in order to isolate any renoprotective effect from any concomitant effect on blood glucose homeostasis. Methods Sprague‐Dawley rats were injected with streptozotocin (STZ) (50 mg kg−1) and when stable started on metformin treatment (250 mg kg−1) in the drinking water. Rats were prepared for in vivo measurements 25 to 30 days after STZ injection, where renal function, including glomerular filtration rate and sodium transport, was estimated in anesthetized rats. Intrarenal oxygen tension was measured using oxygen sensors. Furthermore, mitochondrial function was assessed in mitochondria isolated from kidney cortex and medulla analysed by high‐resolution respirometry, and superoxide production was evaluated using electron paramagnetic resonance. Results Insulinopenic rats chronically treated with metformin for 4 weeks displayed improved medullary tissue oxygen tension despite of no effect of metformin on blood glucose homeostasis. Metformin reduced UCP2‐dependent LEAK and differentially affected medullary mitochondrial superoxide radical production in control and diabetic rats. Conclusions Metformin attenuates diabetes‐induced renal medullary tissue hypoxia in an animal model of insulinopenic type 1 diabetes. The results suggest that the mechanistic pathway to attenuate the diabetes‐induced medullary hypoxia is independent of blood glucose homeostasis and includes reduced UCP2‐mediated mitochondrial proton LEAK.

Metformin Attenuates Renal Tubulointerstitial Fibrosis via Upgrading Autophagy in the Early Stage of Diabetic Nephropathy

“…The therapeutic effects of metformin on slowing the progression of DN have been another spotlight apart from its hypoglycemic effects [28][29][30]. An initial objective of the study was to investigate the effect of metformin on TIF because it is still controversial [31].…”

“…As well known, DN was characterized by the development of tubulointerstitial brosis (TIF) and impaired renal function [7][8][9]. Evidence proved that RTECs underwent EMT during DN, leading to the over deposition of ECM after injury and further deterioration of TIF [10][11][12].…”

Metformin: the updated protective property in kidney disease

“…Metformin can overcome hyperglycemia-induced insulin resistance in podocytes by promoting the expression and function of SIRT1 and AMPK [103]. Furthermore, metformin attenuates DMinduced renal medullary tissue hypoxia by inhibiting uncoupling protein 2 in insulinopenic type 1 diabetes rats [104]. As mentioned above, metformin also modulates the interplay between oxidative stress, lipotoxicity, fibrosis, and aging in DKD to delay renal exacerbation.…”

Significance of Metformin Use in Diabetic Kidney Disease

“…They also found that metformin reduced the ATP production and oxygen consumption rates and increased cellular oxygen tension in T2D rats [ 62 ]. Christensen et al showed that metformin improves medullary hypoxia and attenuates mitochondrial superoxide radical production by inhibiting uncoupling protein-(UCP) 2 under diabetic conditions [ 69 ]. Senescence of renal cells has been implicated in the pathogenesis of DKD [ 70 ].…”