PMID- 25658916
OWN - NLM
STAT- MEDLINE
DCOM- 20160503
LR  - 20220112
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 2
DP  - 2015
TI  - A cationic-independent mannose 6-phosphate receptor inhibitor (PXS64) ameliorates 
      kidney fibrosis by inhibiting activation of transforming growth factor-beta1.
PG  - e0116888
LID - 10.1371/journal.pone.0116888 [doi]
LID - e0116888
AB  - The activity of transforming growth factor-beta1 (TGF-beta1) 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 TGFbeta1+/- 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 TGFbeta 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-beta1. 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-beta1.
FAU - Zhang, Jie
AU  - Zhang J
AD  - Kolling Institute of Medical Research, Sydney, Australia.
FAU - Wong, Muh Geot
AU  - Wong MG
AD  - Kolling Institute of Medical Research, Sydney, Australia.
FAU - Wong, May
AU  - Wong M
AD  - Kolling Institute of Medical Research, Sydney, Australia.
FAU - Gross, Simon
AU  - Gross S
AD  - Kolling Institute of Medical Research, Sydney, Australia.
FAU - Chen, Jason
AU  - Chen J
AD  - Royal North Shore Hospital, St. Leonards, Australia.
FAU - Pollock, Carol
AU  - Pollock C
AD  - Kolling Institute of Medical Research, Sydney, Australia.
FAU - Saad, Sonia
AU  - Saad S
AD  - Kolling Institute of Medical Research, Sydney, Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150206
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Mannosides)
RN  - 0 (Organophosphonates)
RN  - 0 (PXS64 compound)
RN  - 0 (Prodrugs)
RN  - 0 (SMAD2 protein, human)
RN  - 0 (Smad2 Protein)
RN  - 0 (Transforming Growth Factor beta)
SB  - IM
EIN - PLoS One. 2022 Jan 12;17(1):e0262725. PMID: 35020773
MH  - Animals
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Fibrosis/*drug therapy/genetics/metabolism/pathology
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Kidney/drug effects/*pathology
MH  - Kidney Tubules/cytology/*drug effects/metabolism
MH  - Male
MH  - Mannosides/*pharmacology
MH  - Mice, Inbred C57BL
MH  - Neutrophils/drug effects
MH  - Organophosphonates/*pharmacology
MH  - Prodrugs/pharmacology
MH  - Smad2 Protein/metabolism
MH  - Transforming Growth Factor beta/*metabolism/pharmacology
MH  - Ureteral Obstruction/pathology
PMC - PMC4319899
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2015/02/07 06:00
MHDA- 2016/05/04 06:00
PMCR- 2015/02/06
CRDT- 2015/02/07 06:00
PHST- 2014/09/03 00:00 [received]
PHST- 2014/12/16 00:00 [accepted]
PHST- 2015/02/07 06:00 [entrez]
PHST- 2015/02/07 06:00 [pubmed]
PHST- 2016/05/04 06:00 [medline]
PHST- 2015/02/06 00:00 [pmc-release]
AID - PONE-D-14-39716 [pii]
AID - 10.1371/journal.pone.0116888 [doi]
PST - epublish
SO  - PLoS One. 2015 Feb 6;10(2):e0116888. doi: 10.1371/journal.pone.0116888. 
      eCollection 2015.