Semicarbazide-sensitive amine oxidase (SSAO) is an
enzyme known for its dual function in mediating
inflammation and
reactive oxygen species production. However, the role of SSAO inhibitors in limiting kidney
fibrosis is unclear. We aimed to determine the effectiveness of a SSAO inhibitor (SSAOi; PXS4728A) as an antifibrotic agent using a 7-day unilateral ureteric obstruction (UUO) model of acute kidney
fibrosis in 6- to 8-wk-old mice. The experimental groups were 1)
Sham operated; 2) UUO; 3) UUO+SSAOi (2 mg/kg); 4) UUO+telmisartan, an
angiotensin receptor blocker (3 mg/kg); and 5) UUO+SSAOi+
telmisartan. Kidney tissue was analyzed for histological evidence of tubulointerstitial
fibrosis,
nitrotyrosine staining, and
mRNA expression of markers associated with
fibrosis and
inflammation. Kidney SSAO activity was determined by radiometric [(14)C]
benzylamine methodology. Our results show that SSAOi effectively suppresses UUO-mediated SSAO activity. Extracellular matrix markers, namely,
fibronectin,
collagen IV
protein, and
nitrotyrosine staining, were lower in UUO+SSAOi mice compared with untreated UUO mice. This was consistent with the attenuated
mRNA expression of
collagen IV and
fibronectin. SSAOi effectively inhibited
transforming growth factor-β1 (TGF-β1) and
monocyte chemoattractant protein-1 (MCP-1) expression to a similar extent to that observed with
telmisartan. Individually, SSAOi and
telmisartan induced a reduction in interstitial leukocyte and macrophage accumulation. However, the combination of SSAOi and
telmisartan was more effective at reducing inflammatory cell infiltration. These results demonstrate that SSAO inhibition significantly suppresses profibrotic and proinflammatory
cytokine secretion, reduces oxidative stress, and limits inflammatory cell accumulation and extracellular matrix expression in an acute model of renal
fibrosis.