Key result
In renal cell models, profibrogenic agonists up-regulated DJ-1 expression, and DJ-1 overexpression increased cell resistance to oxidative stress, highlighting its role in renal fibrosis.
Protein DJ-1 plays a key role in the anti-oxidative stress response in renal cells, with its acidic group being crucial for ROS scavenging activity.
DJ-1 may protect renal cells from oxidative stress; leaves open its therapeutic targeting in human renal fibrosis.
In the pathogenesis of renal fibrosis, oxidative stress (OS) enhances the production of reactive oxygen species (ROS) leading to sustained cell growth, inflammation, excessive tissue remodelling and accumulation, which results in the development and acceleration of renal damage. In our previous work (Eltoweissy et al., 2011) we established protein DJ-1 (PARK7) as an important ROS scavenger and key player in renal cell response to OS. In the present study we investigated the impact of profibrogenic agonists on DJ-1 and shed light on the role of this protein in renal fibrosis. Treatment of renal fibroblasts and epithelial cells with the profibrogenic agonist ANG II or PDGF resulted in a significant up-regulation of DJ-1 expression parallel to an increase in the expression of fibrosis markers. Monitoring of DJ-1 expression in kidney extract and tissue sections from a renal fibrosis mouse model (Col4a3-deficient) revealed a disease grade dependent regulation of the protein. Overexpression of DJ-1 prompted cell resistance to OS in both fibroblasts and epithelial cells. Furthermore overexpression of DJ-1, involved in ROS scavenging, in which glutamic acid 18 (E18) is mutated to either to aspartic acid (D) or glutamine (Q) resulted in a significant increase in cell death under OS in the case of E18D mutation, whereas E18Q mutation did not impact significantly the cell response to OS, revealing the importance of the acidic group for the ROS scavenging activity of the DJ-1 protein more than the nature of the amino acid itself. Affinity precipitation of interaction partners of DJ-1 and its mutants revealed an important role of annexin A1 and A5 in the mechanism of action of DJ-1 in anti-oxidative stress response.
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Eltoweissy et al. (2016) studied Renal fibrosis. DJ-1 overexpression and mutation was evaluated on Cell resistance to oxidative stress and DJ-1 expression. In renal cell models, profibrogenic agonists up-regulated DJ-1 expression, and DJ-1 overexpression increased cell resistance to oxidative stress, highlighting its role in renal fibrosis.
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