Semicarbazide-sensitive amine oxidase inhibition ameliorates albuminuria and glomerulosclerosis but does not improve tubulointerstitial fibrosis in diabetic nephropathy.

May Yw Wong,Amgad Zaky,Sonia Saad,Muh Geot Wong,Heidi Schilter,Wolfgang Jarolimek,Anthony Gill,Stefanie Stangenberg,Carol Pollock,Jaap A Joles

doi:10.1371/journal.pone.0234617

May Yw Wong, Amgad Zaky + Show 8 more

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https://doi.org/10.1371/journal.pone.0234617

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Abstract

Semicarbazide-sensitive amine oxidase (SSAO) is an enzyme with a unique dual function in controlling inflammation as well as reactive oxygen species (ROS) generation. We have demonstrated benefit of SSAO inhibition in acute kidney fibrosis. However the function of SSAO in chronic kidney disease (CKD) and diabetic kidney disease (DKD) is yet to be determined. We aimed to assess the effectiveness of a SSAO inhibitor (SSAOi; PXS-4728A) as an antifibrotic agent using a diabetic model of CKD. Diabetic mice were treated with SSAOi for 24 weeks and outcomes compared with untreated diabetic mice and telmisartan treated animals as a standard of care comparator. Extracellular matrix markers, fibronectin and oxidative stress, were downregulated in diabetic mice treated with SSAOi compared with untreated diabetic mice. Expression of the pan-leukocyte marker CD45 was also supressed by SSAOi. SSAO inhibition in diabetic mice resulted in a significant reduction in glomerulosclerosis and associated albuminuria compared to untreated diabetic mice. However, the effect of SSAO inhibition was less obvious in the tubulointerstitial compartment than in the glomeruli. Therefore, SSAO may be a potential target for diabetic glomerulosclerosis.

Highlights

Diabetic kidney disease (DKD) is the leading cause for chronic kidney disease (CKD) with an ever increasing rate
We demonstrated using an acute model of renal fibrosis that sensitive amine oxidase (SSAO) inhibition can effectively impair profibrotic and proinflammatory cytokine secretion, limit inflammatory cell accumulation, extracellular matrix expression, and oxidative stress
DKD is associated with the SSAO inhibition ameliorates albuminuria and glomerulosclerosis initiation of various pathways including inflammatory pathways that result in the evolution of ESKD

Summary

Introduction

Diabetic kidney disease (DKD) is the leading cause for chronic kidney disease (CKD) with an ever increasing rate. The management approach to DKD to date is restricted to the inhibition of the renin angiotensin aldosterone system (RAAS) [1], and more recently to blockade of sodium-glucose linked transporter-2[2]. This approach has limitations with ongoing risk of progression to end stage renal failure (ESRF).

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