Journal
ANTIOXIDANTS
Volume 12, Issue 8, Pages -Publisher
MDPI
DOI: 10.3390/antiox12081541
Keywords
CCN2; NLRP3 inflammasome; RIPK3; inflammation; NRF2; oxidation; acute kidney injury
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Inflammation is a key characteristic of kidney diseases, and the NLRP3/Inflammasome, RIPK3, and NRF2/oxidative pathways are involved in kidney inflammation regulation. CCN2 is a fibrotic biomarker and mediator of kidney damage, and its role in the NLRP3/RIPK3/NRF2 pathways has not been evaluated.
Inflammation is a key characteristic of both acute and chronic kidney diseases. Preclinical data suggest the involvement of the NLRP3/Inflammasome, receptor-interacting protein kinase-3 (RIPK3), and NRF2/oxidative pathways in the regulation of kidney inflammation. Cellular communication network factor 2 (CCN2, also called CTGF in the past) is an established fibrotic biomarker and a well-known mediator of kidney damage. CCN2 was shown to be involved in kidney damage through the regulation of proinflammatory and profibrotic responses. However, to date, the potential role of the NLRP3/RIPK3/NRF2 pathways in CCN2 actions has not been evaluated. In experimental acute kidney injury induced with folic acid in mice, CCN2 deficiency diminished renal inflammatory cell infiltration (monocytes/macrophages and T lymphocytes) as well as the upregulation of proinflammatory genes and the activation of NLRP3/Inflammasome-related components and specific cytokine products, such as IL-1 beta. Moreover, the NRF2/oxidative pathway was deregulated. Systemic administration of CCN2 to C57BL/6 mice induced kidney immune cell infiltration and activated the NLRP3 pathway. RIPK3 deficiency diminished the CCN2-induced renal upregulation of proinflammatory mediators and prevented NLRP3 modulation. These data suggest that CCN2 plays a fundamental role in sterile inflammation and acute kidney injury by modulating the RIKP3/NLRP3/NRF2 inflammatory pathways.
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