Lysyl oxidase-like 2 inhibition ameliorates glomerulosclerosis and albuminuria in diabetic nephropathy

Diabetic nephropathy is characterised by the excessive amount of extracellular matrix in glomeruli and tubulointerstitial space. Lysyl oxidase-like 2 (LOXL2) is elevated in renal fibrosis and known to play key roles in ECM stabilisation by facilitating collagen cross-links, epithelial to mesenchymal...

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Published in:Scientific reports 2018-06, Vol.8 (1), p.9423-10, Article 9423
Main Authors: Stangenberg, Stefanie, Saad, Sonia, Schilter, Heidi C., Zaky, Amgad, Gill, Anthony, Pollock, Carol A., Wong, Muh Geot
Format: Article
Language:English
Subjects:
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Collagen (type I)
Cross-linking
Diabetes
Diabetes mellitus
Diabetic nephropathy
Extracellular matrix
Fibronectin
Fibrosis
Humanities and Social Sciences
Lysyl oxidase
Mesenchyme
multidisciplinary
Nephropathy
Rodents
Science
Science (multidisciplinary)
Streptozocin
Structure-function relationships
Therapeutic applications
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Summary:Diabetic nephropathy is characterised by the excessive amount of extracellular matrix in glomeruli and tubulointerstitial space. Lysyl oxidase-like 2 (LOXL2) is elevated in renal fibrosis and known to play key roles in ECM stabilisation by facilitating collagen cross-links, epithelial to mesenchymal transition and myofibroblast activation. Thus, targeting LOXL2 may prove to be a useful strategy to prevent diabetic nephropathy. We explored the renoprotective effect of a selective small molecule LOXL2 inhibitor (PXS-S2B) in a streptozotocin-induced diabetes model. Diabetic mice were treated with PXS-S2B for 24 weeks and outcomes compared with untreated diabetic mice and with telmisartan treated animals as comparator of current standard of care. Diabetic mice had albuminuria, higher glomerulosclerosis scores, upregulation of fibrosis markers and increased renal cortical LOXL2 expression. Treatment with PXS-S2B reduced albuminuria and ameliorated glomerulosclerosis. This was associated with reduced expression of glomerular fibronectin and tubulointerstitial collagen I. The renoprotective effects of both PXS-S2B and telmisartan were more marked in the glomerular compartment than in the tubulointerstitial space. The study reveals that LOXL2 inhibition was beneficial in preserving glomerular structure and function. Thus, LOXL2 may be a potential therapeutic target in diabetic nephropathy.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-27462-6