SUMO E3 Ligase PIASy Mediates High Glucose-Induced Activation of NF-B Inflammatory Signaling in Rat Mesangial Cells.

Background: Sumoylation is extensively involved in the regulation of NF-B signaling. PIASy, as a SUMO E3 ligase, has been proved to mediate sumoylation of IB kinase (IKK) and contribute to the activation of NF-B under genotoxic agent stimulation. However, the association of PIASy and NF-B signaling in the pathogenesis of diabetic nephropathy (DN) has not been defined.

Methods: Rat glomerular mesangial cells (GMCs) were stimulated by high glucose; siRNA was constructed to silence the expression of PIASy; the expression of PIASy, SUMO isoforms (SUMO1, SUMO2/3), and NF-B signaling components was analyzed by Western blot; the interaction between IKK and SUMO proteins was detected by coimmunoprecipitation; and the release of inflammatory cytokines MCP-1 and IL-6 was assayed by ELISA.

Results: High glucose significantly upregulated the expression of PIASy, SUMO1, and SUMO2/3 in a dose- and time-dependent manner ( < 0.05), induced the phosphorylation and sumoylation of IKK ( < 0.05), and then triggered NF-B signaling whereas MCP-1 and IL-6 were released from GMCs ( < 0.05). Moreover, these high glucose-induced effects were observably reversed by siRNA-mediated knockdown of PIASy ( < 0.05).

Conclusion: The SUMO E3 ligase PIASy mediates high glucose-induced activation of NF-B inflammatory signaling, suggesting that PIASy may be a potential therapeutic target of DN.