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theses

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the United States. Hyperglycemia and hemodynamic aberrations contribute to DN. But growing evidence identifies oxidative stress, inflammation, and epigenetics as playing important roles in the pathogenesis of DN. To ameliorate DN, strategies to mitigate excessive oxidative stress and inflammation or alter epigenetics have been proposed. One strategy involves the activation of Nrf2, a transcription factor that regulates the antioxidant response. Nrf2 has been discovered to play a protective role against DN and activation of Nrf2 can lower oxidative stress and inflammation in many different disease models. Development of Nrf2 activators for treating DN have been tested in clinical studies and showed promising results. However, their development has been hampered by increased adverse events. As an alternative, dietary phytochemicals have been studied as safer modalities for reducing oxidative stress and inflammation due to their antioxidant and anti-inflammatory properties. Our group has investigated the use of a novel phytochemical, MIC-1, an isothiocyanate found in Moringa oleifera, and its potential in DN. MIC-1 upregulated the Nrf2 antioxidant response in HepG2C8 cells to increase antioxidant genes in addition to reducing inflammation in RAW264.7 cells. In an in vitro HK-2 cell culture model of DN, MIC-1 reduced high glucose induced oxidative stress and reverse activation of the upstream regulator, TGFβ1, a key driver in DN development and progression. Though oxidative stress and inflammation play important roles in DN, epigenetics have also been identified to contribute to DN. One type of epigenetic modification, DNA methylation, plays an important role in gene regulation of many diseases including cancer and diabetes. Our study showed that in an in vivo model of early DN, DNA methylation alterations can influence gene expression that contribute towards driving DN progression. Evidence for use of dietary phytochemicals found commonly in over-the-counter medicines in human are limited. To assess the potential of dietary phytochemicals in humans, a small study on a single dose of oral curcumin in healthy human volunteers was performed. Parent curcumin was not detectable in subjects’ plasma. However, levels of curcumin metabolite were detected along with increases in antioxidant genes and decreases in epigenetic modifying enzymes. Collectively, dietary phytochemicals modulate antioxidant and epigenetic genes that could contribute to ameliorating DN. The long-term goal for this research is to understand the epigenetic events involved in DN and to develop safer alternatives using dietary phytochemicals such as isothiocyanates and curcumin to influence oxidative stress, inflammation, and epigenetic alterations.

ETD_10371

Ph.D.

Includes bibliographical references

doi:10.7282/t3-s6th-9z64

ETD doctoral

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