Nuclear factor-erythroid 2-related factor 2 (Nrf2) is one Gemcitabine price of the most important cellular defense mechanisms against oxidative stress. NAD(P)H quinine oxidoreductase (NQO1), was the well-studied Nrf2 target genes that are up-regulated through the antioxidant response element regulatory element in response to oxidative stress. The aims of the research was investigated
the effects of Zn deficiency on diabetes-induced renal oxidative damage, inflammation and fibrosis, and the relation with Nrf2 and NQO1. Methods: Type 1 diabetes was induced in FVB mice with multiple low doses of streptozotocin. Once hyperglycemia was established, diabetic and age matched control mice were treated with and without Zn chelator, N, N, N′, N′-tetrakis (2-pyridylemethyl) ethylenediamine (TPEN) at 5 mg/kg daily for 4 months. Renal oxidative damage, inflammation
and fibrosis mice were examined by histopathological observation, Naphthol AS-D Chloroacetate esterase assay, immunofluorescent staining, and Western blotting assay. Human renal tubular HK 11 cells were treated by TPEN and Zn, the expression of Nrf2 and NQO1 were examined by immunofluorescent and Western bloting assay. Results: Chronic treatment with TPEN significantly JNK inhibitor for decreased renal Zn levels in both diabetic and control mice. Compared to group with diabetes or TPEN alone, Diabetes/TPEN group showed a significant decrease in Nrf2 expression along with significant increases of renal oxidative damage (protein nitration and lipid oxidation), renal inflammation [infiltrated inflammatory cells and expression of plasminogen activator inhibitor-1(PAI-1) ], and renal fibrosis [PAS staining and expression of profibrotic mediator connective tissue growth factor (CTGF)]. Mechanistic study with human renal tubular HK 11 cells showed that TPEN removal of intracellular Zn decreased
Nrf2 and NQO1 expression, which could be significantly attenuated by Zn supplementation. Conclusion: These results indicated that Zn deficiency significantly enhanced diabetes-induced renal oxidative damage, inflammation and structural remodeling through downregulation of Nrf2 expression and function. CHOI SOO Y1, LIM SUN W2, YOO EUN J1, SANADA SATORU3, LEE HWAN H1, KWON MI J1, LEE-KWON WHASEON1, KWON HYUG M1,3 1UNIST; 2Catholic University of Korea; 3University of Maryland Introduction: We reported previously that, in patients with ∼30 years of type 1 diabetes, proteinuria was associated with ∼50% higher activity of the TonEBP transcription factor in monocytes (1).