1Kolling Institute, University of Sydney, Royal North Shore Hospital, Sydney, New South Wales

Aim: To define the role of RIPK1 inhibition in alleviating renal fibrogenesis.

Background: Current therapies for renal fibrosis are largely ineffective. Therefore, identification of novel therapeutic targets is essential. RIPK1 is identified as a crucial regulator of necrosis, apoptosis and inflammation, which have been well recognised to be involved in renal fibrogenesis. To date, the role of RIPK1 in renal fibrosis has not been reported.

Methods: RIPK1 expression levels were determined in normal and diabetic mice kidney tissue by immunohistochemistry. In vitro, HK2 cells (human proximal tubular cells) were incubated with/without TGF-β1 (2 ng/ml) in the absence or presence of 80µM nec-1s (a selective pharmacological inhibitor of RIPK1) for 48 hours. Supernatant, cell lysate and total RNA were collected for Western blotting and quantitative RT-PCR analysis.

Results: Renal tubular cells from diabetic mice had significantly higher expression level of RIPK1 compared to normal mice. TGF-β induced the protein expression of collagen I, collagen III, collagen IV, and fibronectin (n=4; all P<0.05) compared to control, which were attenuated by nec-1s (n=4; all P<0.05). Quantitative RT-PCR showed consistent results that TGF-β increased the mRNA level of collagen I, IV fibronectin, which were partially reversed by nec-1s in HK2 cells (n=4; all P<0.05). In addition, nec-1s decreased the expression level of phospho-p38 MAPK and phospho-p44/42 MAPK (Erk1/2) (n=4; both P<0.05), while TGF-β increased phosphorylation ratio on both kinases (n=4; both P<0.05).

Conclusions: These results suggest that RIPK1 may be a potential novel target in renal fibrosis.


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