The crosstalk between Sirt1 and Keap1/Nrf2/ARE anti-oxidative pathway forms a positive feedback loop to inhibit FN and TGF-β1 expressions in rat glomerular mesangial cells

Journal Article · Fri Dec 15 04:00:00 EST 2017 · Experimental Cell Research

DOI:https://doi.org/10.1016/J.YEXCR.2017.09.042· OSTI ID:22901309

Huang, Kaipeng ^[1]; Gao, Xiang ^[2]; Wei, Wentao ^[3]

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1. Drug Clinical Trial Institution, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou 510060 (China)
2. Department of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080 (China)
3. Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006 (China)

Highlights: • Sirt1 deacetylated and reduced the ubiquitination level of Nrf2 in AGEs-treated GMCs. • Sirt1 promoted Keap1/Nrf2/ARE pathway activation to decrease FN and TGF-β1 levels. • Nrf2 also regulated Sirt1 at protein expression and deacetylase activity levels. • Sirt1 and Keap1/Nrf2/ARE pathway forms a positive feedback to prevent FN and TGF-β1 expressions. Oxidative stress aroused by advanced glycation-end products (AGEs) is a culprit in the pathological progression of diabetic nephropathy. Both Sirt1 and the Keap1/Nrf2/ARE anti-oxidative pathway exert crucial inhibitory effects on the development of diabetic nephropathy. Our previous study has confirmed that Sirt1 activation can inhibit the upregulation of fibronectin (FN) and transforming growth factor-β1 (TGF-β1) by promoting Keap1/Nrf2/ARE pathway in glomerular mesangial cells (GMCs) challenged with AGEs. However, the underlying mechanism needs further investigation. Here, we found that concomitant with deacetylating and reducing the ubiquitination levels of Nrf2, Sirt1 significantly enhanced the activity of Keap1/Nrf2/ARE pathway including decreasing Keap1 expression, promoting the nuclear content, ARE-binding ability, and transcriptional activity of Nrf2, augmenting the protein levels of heme oxygenase 1, a target gene of Nrf2, which eventually quenched ROS overproduction and alleviating FN and TGF-β1 accumulation in AGEs-treated GMCs. And depletion of Nrf2 blocked those renoprotective effects of Sirt1. Interestingly, Nrf2 also positively regulated Sirt1 at the protein expression and deacetylase activity levels as evidenced by tert-Butylhydroquinone and specific siRNA targeting Nrf2 to downregulate FN and TGF-β1. In conclusion, the current study basically demonstrated that the crosstalk between Sirt1 and Keap1/Nrf2/ARE anti-oxidative pathway forms a positive feedback loop to inhibit the protein expressions of FN and TGF-β1 in AGEs-treated GMCs.

• OSTI ID: 22901309
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 1 Vol. 361; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACTIVITY LEVELS
BIOLOGICAL ACCUMULATION
BIOLOGICAL STRESS
FEEDBACK
GROWTH FACTORS
HEME
OXIDATION
OXYGENASES
RATS