BLOCKADE OF RIPK3 MODIFIES RENAL FIBROGENESIS THROUGH INHIBITION OF NF ΚB

Y SHI1,  C HUANG1, X CHEN1, C POLLOCK1
1Kolling Institute, Royal North Shore Hospital, St Leonards, Australia

Aim: To define the role of receptor-interacting protein kinase 3 (RIPK3) in alleviating renal fibrogenesis.
Background: Current therapies for renal fibrosis are largely ineffective. Therefore, identification of novel therapeutic targets is essential. RIPK3 is identified as a crucial regulator of Interleukin-1 (IL-1) secretion via the necroptotic pathway and the nuclear factor NF κB pathway, which have been well recognised to be involved in renal fibrogenesis by regulating TGF-β. To date, the function of RIPK3 in renal fibrosis remains unclear.
Methods: C57BL/6 wild-type mice and C57BL/6 RIPK3 gene knock out (RIPK3-/-) mice were used in the study. Renal fibrosis was induced with folic acid (250 mg/kg) and animals were killed at 28th day after folic acid injection. Dabrafenib (2.5 μg/hr) was used as a pharmacological inhibitor of RIPK3.
Results: FA nephropathy led to a significant renal injury within in the kidney cortex characterized by tubular dilation, tubule atrophy, cast formation and inflammatory cell infiltration (p<0.0001). These pathological changes were accompanied by an elevation in expression of pro‐fibrotic markers (collagen I, p<0.05; collagen III, p<0.05; TGF-β, p<0.0001), myofibroblast activation (α-SMA, p<0.0001) and inflammatory response (MCP-1, p<0.0001; F4/80, p<0.0001, phosphorylated p65, p<0.01). Genetic ablation of RIPK3 or RIPK3 inhibition abrogated all markers of renal injury (all p<0.05), fibrotic responses (all p<0.05) and inflammation (all p<0.05). However, IL-1 production was not modified.
Conclusions: These results suggest that RIPK3 may be a potential novel target in renal fibrosis. However, the beneficial effects are likely to be mediated through inhibition of NFKB and independent of the necroptotic pathway.


Biography:
Ying Shi is is a PhD candidate in Medicine at the University of Sydney under the supervision of Prof. Carol Pollock. Her research focuses on identifying novel therapeutic target for renal fibrosis.

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