Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db mice as a model of type 2 diabetes

Abstract

Aims/hypothesis Increased oxygen consumption results in kidney tissue hypoxia, which is proposed to contribute to the development of diabetic nephropathy. Oxidative stress causes increased oxygen consumption in type 1 diabetic kidneys, partly mediated by uncoupling protein-2 (UCP-2)-induced mitochondrial uncoupling. The present study investigates the role of UCP-2 and oxidative stress in mitochondrial oxygen consumption and kidney function in db/db mice as a model of type 2 diabetes. Methods Mitochondrial oxygen consumption, glomerular filtration rate and proteinuria were investigated in db/db mice and corresponding controls with and without coenzyme Q10 (CoQ10) treatment. −1 ). UCP-2 protein levels were similar in untreated control and db/db mice (67± 9 vs 67± 4 optical density; OD) but were reduced in CoQ10 treated groups (43±2 and 38±7 OD). Conclusions/interpretation db/db mice displayed oxidative stress-mediated activation of UCP-2, which resulted in mitochondrial uncoupling and increased oxygen consumption. CoQ10 prevented altered mitochondrial function and morphology, glomerular hyperfiltration and proteinuria in db/db mice, highlighting the role of mitochondria in the pathogenesis of diabetic nephropathy and the benefits of preventing increased oxidative stress.

Antioxidant treatment attenuates lactate production in diabetic nephropathy

“…The present study demonstrates, using a non-invasive imaging method that only requires an intravenous injection of the tracer, a novel link between oxidative stress and pseudohypoxia in the diabetic kidney. This provides an additional mechanistic explanation for the beneficial effects of antioxidant treatment on diabetic kidney function (14,17).…”

Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

“…Mitochondrial uncoupling through UCP-2 is activated by oxidative stress, 13,14 and we have previously reported markedly increased UCP-2 activity in the diabetic kidney, resulting in increased mitochondrial QO 2 . 15,16 Preventing increased uncoupled QO 2 , therefore, seems feasible to minimize oxygen wasting in the diabetic kidney.…”

“…Mitochondria was isolated from kidney cortex, and mitochondrial oxygen consumption was recorded using high-resolution respirometry using an Oroboros O2K (Oroboros Instruments, Innsbruck, Austria) and corrected for protein concentration. 15 Mitochondria function was determined as state 4 respiration in the presence of glutamate (10 mmol/L), state 3 respiration after the addition of 400 mmol/L ADP, and respiratory control ration calculated as state 3 over state 4 respiration. Mitochondrial uncoupling was determined as leak respiration (i.e., respiration in the presence of ATP-synthase inhibitor oligomycin [12 mg/mg protein]), and responsible mechanisms were evaluated as the sensitivity of leak respiration to guanosine diphosphate (GDP; 500 mmol/L; inhibitor of UCP) and carboxyatractylate (CAT; 0.5 mmol/L; inhibitor of ANT).…”

Comparative Effects of Statins on the Kidney Function in Patients with Type 2 Diabetes

“…Therefore, the other three statins are thought to more strongly inhibit the production of CoQ10 in extrahepatic cells than pravastatin. Recent basic studies have clearly shown that CoQ10 treatment prevents the development of DKD by reducing oxidative stress in db/db mice employed as a model of type 2 diabetes 21,22) . In light of these findings, the superiority of pravastatin demonstrated in the present study may be partly explained by differences in CoQ10 production in extrahepatic cells as a result of differences in lipophilicity.…”