Ursodeoxycholic Acid Ameliorated Diabetic Nephropathy by Attenuating Hyperglycemia-Mediated Oxidative Stress

Abstract

Oxidative stress has a great role in diabetes and diabetes induced organ damage. Endoplasmic reticulum (ER) stress is involved in the onset of diabetic nephropathy. We hypothesize that ER stress inhibition could protect against kidney injury through anti-oxidative effects. To test whether block ER stress could attenuate oxidative stress and improve diabetic nephropathy in vivo and in vitro, the effect of ursodeoxycholic acid (UDCA), an ER stress inhibitor, on spontaneous diabetic nephropathy db/db mice, ER stress inducer or high glucose-triggered podocytes were studied. Mice were assigned to 3 groups (n 6 per group): control group (treated with vehicle), db/db group (treated with vehicle), and UDCA group (db/db mice treated with 40 mg/ kg/d UDCA). After 8 weeks treatment, mice were sacrificed. Blood and kidneys were collected for the assessment of albumin/creatinine ratio, blood urea nitrogen (BUN), serum creatinine (SCr), insulin, total cholesterol, triglyceride, low density lipoprotein cholesterol (LDL-C), oxidized LDL-C, high density lipoprotein cholesterol (HDL-C), non-esterified fatty acid (NEFA), superoxide dismutase (SOD), catalase (CAT), methane dicarboxylic aldehyde (MDA), the expressions of SOD isoforms and glutathione peroxidase 1, as well as histopathological examination. In addition, generation of reactive oxygen species (ROS) was detected by 2′7′-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence. The results showed that UDCA alleviated renal ER stress-evoked cell death, oxidative stress, renal dysfunction, ROS production, upregulated the expression of Bcl-2 and suppressed Bax in vivo and in vitro. Hence, inhibition ER stress diminishes oxidative stress and exerts renoprotective effects.Key words diabetic nephropathy; podocyte; oxidative stress; reactive oxygen species Diabetic mellitus is a global health problem in which blood glucose is persistently elevated and generates a cascade of events in organ including kidney.1,2) The population with diabetes has been increasing worldwide and diabetic nephropathy (DN) now is a leading cause of end-stage renal failure.3)The mechanisms by which hyperglycemia contributes to kidney remain limited due to various factors modulate the plasma glucose in the body. The management of DN is based on the control of plasma glucose levels. 4) Reviewing number of studies demonstrates that reactive oxygen species (ROS), associated with increased plasma glucose, has been implicated in the pathogenesis of DN, which results in the over-production of extracellular matrix proteins, mitochondrial damage and glomeruli injury.5-8) Therefore, oxidative stress attenuation is an important pathway in DN prevention. 9)The endoplasmic reticulum (ER) regulates the folding of secretory and intracellular calcium.10) Excessive unfolded proteins in the lumen of ER produces stress and contributed to the disorder of intracellular signal transduction pathways. 11)A number of pathophysiological conditions are associated with ER stress included diabetes. ER stress is a key mediator of β...

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