title: A cationic-independent mannose 6-phosphate receptor inhibitor (PXS64) ameliorates kidney fibrosis by inhibiting activation of transforming growth factor-β1.
abstract: The activity of transforming growth factor-β1 (TGF-β1) is regulated by its conversion from the latent to the active form. We have previously shown that the conversion is at least in part mediated by the cationic-independent mannose 6-phosphate receptor (CI-M6PR), as the CI-M6PR inhibitor, PXS-25 has anti-fibrotic properties in human kidney tubular (HK-2) cells under high glucose conditions. However, its clinical use is limited by low bioavailability. Our aim was to determine the effects of PXS64, a pro-drug of PXS25, in in vitro and in vivo models of renal fibrosis. HK-2 cells were exposed to latent TGFβ1+/- PXS64 for 48 hours. The mRNA and protein levels of pro-fibrotic and pro-inflammatory markers were determined. A 7 day unilateral ureteric obstruction (UUO) model was used and the following experimental groups were studied: (i) Sham operated, (ii) UUO, (iii) UUO + telmisartan (iv) UUO + PSX64. HK-2 cells exposed to PXS64 reduced TGFβ mediated effects on collagen IV, fibronectin, macrophage chemotactic protein-1 (MCP-1) and phospho-smad2 protein expression, consistent with inhibition of the conversion of latent to active TGF-β1. PXS 64 treated UUO mice had a lower tubulointerstitial fibrosis index, collagen IV and fibronectin protein and mRNA expression when compared to untreated UUO mice. In addition, these animals had lower MCP-1 mRNA expression, reduced inflammarory cell infiltrate, as indicated by fewer CD45, F4/80 positive cells, and reduced phospho-Smad2 protein expression when compared to untreated UUO animals. Our data demonstrates that PSX64 is an effective anti-fibrotic agent by inhibiting the activation of latent TGF-β1.
authors: Kolling Institute of Medical Research, Sydney, Australia.
authors: Jie
authors: J
authors: Zhang
authors: Kolling Institute of Medical Research, Sydney, Australia.
authors: Muh Geot
authors: MG
authors: Wong
authors: Kolling Institute of Medical Research, Sydney, Australia.
authors: May
authors: M
authors: Wong
authors: Kolling Institute of Medical Research, Sydney, Australia.
authors: Simon
authors: S
authors: Gross
authors: Royal North Shore Hospital, St. Leonards, Australia.
authors: Jason
authors: J
authors: Chen
authors: Kolling Institute of Medical Research, Sydney, Australia.
authors: Carol
authors: C
authors: Pollock
authors: Kolling Institute of Medical Research, Sydney, Australia.
authors: Sonia
authors: S
authors: Saad
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005355:Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008362:Mannosides / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects; D063065:Organophosphonates / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D014517:Ureteral Obstruction / Q000473:pathology
chemical_list: D008362:Mannosides; D063065:Organophosphonates; C000607186:PXS64 compound; D011355:Prodrugs; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta