Prevention of diabetic nephropathy in rats through enhanced renal antioxidative capacity by inhibition of the proteasome.
OBJECTIVE
Oxidative stress may play an important role in the pathogenesis of diabetic nephropathy (DN). Recent studies have shown that the ubiquitin-proteasome pathway (UPP) and oxidative stress have interaction. We aimed to investigate whether inhibiting the proteasome has a preventive effect on DN through suppression of renal oxidative stress.


METHODS
Male Sprague-Dawley rats were randomly divided into three groups: a normal control (NC) group, a streptozotocin-induced DN model group, and a DN plus MG132 (10 μg/kg) treatment group.


RESULTS
Increased 24-h urinary protein excretion rate (UPER) and renal pathological changes were all improved after MG132 administration. Furthermore, enhanced renal 26S proteasome activity and concentration in DN rats were effectively reduced after MG132 administration. Increased p47phox and nitrotyrosine (NT) expressions in kidneys of DN rats were decreased after MG132 treatment. Renal mRNA and protein expressions of NF-E2 related factor 2 (Nrf2) were up-regulated by MG132 in comparison to DN alone. Decreased renal mRNA expression of superoxide dismutase 1 (SOD1), catalase (CAT) and glutathione peroxidase (GPx) in DN rats was heightened after MG132 intervention. Depressed activities of renal SOD, CAT and GPx in DN rats were also improved by MG132 treatment. Increased renal nuclear factor κB (NF-κB) activity was inhibited after MG132 administration in DN rats at the end of 12 weeks.


CONCLUSIONS
Our present data suggest that inhibition of the proteasome by low-dose MG132 has a preventive effect on DN development and progression in rats through the up-regulation of antioxidant genes.
Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, People's Republic of China.
Zhi-Feng
ZF
Luo
Wei
W
Qi
Bing
B
Feng
Jiao
J
Mu
Wei
W
Zeng
Yan-Hong
YH
Guo
Qi
Q
Pang
Zi-Lin
ZL
Ye
Li
L
Liu
Fa-Huan
FH
Yuan
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000473:pathology / Q000652:urine; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control* / Q000652:urine; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007976:Leupeptins / Q000627:therapeutic use*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D011480:Protease Inhibitors / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D011507:Proteinuria / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000975:Antioxidants; D007976:Leupeptins; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde