Background: Novel anti-inflammatory agents targeting early phases of cellular response to injury are increasingly recognised to have a role in mitigating tubulointerstitial fibrosis. Semicarbazide-sensitive amine oxidase (SSAO) is a protein enzyme known for its dualistic role in inflammation by mediating the migration of leukocytes and producing reactive oxygen species. However, the role of SSAO inhibitors in limiting kidney fibrosis is unclear.

Aims: To determine the role of a SSAO inhibitor (PXS-4728A) as an antifibrotic agent using an in vivo model of kidney fibrosis.

Method: A 7 day unilateral ureteric obstruction (UUO) model of acute kidney fibrosis was examined in 6-8 week old mice (20–25g, n=5) with the experimental groups being: (i) Sham operated; (ii) UUO; (iii) UUO+SSAOi (2mg/kg); (iv) UUO +Telmisartan (3mg/kg); and (v) UUO + SSAOi + Telmisartan. Kidney tissue was analysed for histological evidence of tubulointerstitial fibrosis, and specific mRNA expression of fibrosis and inflammation.

Results:  Tubulointerstitial index was lower in SSAOi treated mice compared to UUO (2.1O±0.233 vs 3.65±015; p<0.0001). SSAOi treated mice had lower renal fibronectin and collagen-IV staining compared to UUO mice. This was confirmed by the attenuated mRNA expression of collagen-IV (2.25±1.59 vs 9.62±5.32; p<0.001) and fibronectin (3.20±2.73 vs 12.00±8.47; p<0.05). SSAOi effectively inhibited TGFβ-1 (2.58±1.86 vs 7.39±2.62; p<0.01) and MCP-1 expression (2.69±0.71 vs 7.09± 1.05; p<0.01) (compared to UUO). Telmisartan inhibited TGFβ-1 and MCP-1 to a similar extent to that observed with SSAO inhibition and no synergistic effect was observed.

Conclusion: Our data strongly suggests SSAO inhibition is a novel and effective strategy to inhibit renal fibrosis induced by an acute model of kidney injury.  At the study time of 7 days, it is comparable to the clinically used angiotensin receptor blocker Telmisartan. Future studies will determine its efficacy in a model of diabetic nephropathy.