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

May Yw Wong; Sonia Saad; Muh Geot Wong; Stefanie Stangenberg; Wolfgang Jarolimek; Heidi Schilter; Amgad Zaky; Anthony Gill; Carol Pollock

doi:10.1371/journal.pone.0234617

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

PLoS One. 2020 Jun 18;15(6):e0234617. doi: 10.1371/journal.pone.0234617. eCollection 2020.

Authors

May Yw Wong^{1

2}, Sonia Saad², Muh Geot Wong², Stefanie Stangenberg², Wolfgang Jarolimek³, Heidi Schilter³, Amgad Zaky¹, Anthony Gill^{4

5}, Carol Pollock²

Affiliations

¹ Department of Gastroenterology, Royal North Shore Hospital, St Leonards, Sydney, Australia.
² Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St Leonards, Sydney, New South Wales, Australia.
³ Pharmaxis Ltd, Frenchs Forest, Sydney, New South Wales, Australia.
⁴ Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, Sydney, New South Wales, Australia.
⁵ University of Sydney, Sydney, New South Wales, Australia.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Albuminuria / drug therapy*
Allylamine / analogs & derivatives*
Allylamine / pharmacology
Allylamine / therapeutic use
Amine Oxidase (Copper-Containing) / antagonists & inhibitors*
Animals
Benzamides / pharmacology
Benzamides / therapeutic use*
Diabetes Mellitus, Experimental
Diabetic Nephropathies / drug therapy*
Diabetic Nephropathies / pathology
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / therapeutic use*
Fibronectins / metabolism
Fibrosis
Kidney Glomerulus / drug effects
Kidney Glomerulus / pathology*
Kidney Tubules / drug effects
Kidney Tubules / pathology*
Leukocyte Common Antigens / metabolism
Male
Mice
Mice, Inbred C57BL
Oxidative Stress / drug effects
Renal Insufficiency, Chronic / drug therapy*
Renal Insufficiency, Chronic / pathology
Telmisartan / pharmacology
Telmisartan / therapeutic use

Substances

Benzamides
Enzyme Inhibitors
Fibronectins
PXS-4728A
Allylamine
Amine Oxidase (Copper-Containing)
Leukocyte Common Antigens
Ptprc protein, mouse
Telmisartan

Associated data

figshare/10.6084/m9.figshare.12152625

Grants and funding

Pharmaxis (http://www.pharmaxis.com.au) supported the study in addition to a successful peer reviewed application to the Australian Research Council. WJ provided critical scientific review in the preparation of the manuscript but the content of the manuscript was at all times decided by the academic investigators. They approved the study design but were not directly involved. They were not directly involved with data collection or analysis. HS provided support with the SSAO activity assay. Both WJ and HS reviewed the manuscript prior to publication but were not involved in the decision to publish nor were they involved in the preparation of the manuscript.