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.
Highlights
Tubulointerstitial fibrosis is generally recognized as the final common pathway of chronic kidney disease (CKD) [1]
Active Transforming growth factor-β1 (TGF-β1) interacts with its specific transmembrane TGFβ Type I (TβRI) and type II (TβRII) receptors and activates a cascade of intracellular signaling pathways, including the well-studied small mother against decapentaplegic (Smad), and others pathways such as protein kinase B (AKT) and the extracellular signal-regulated kinase (ERK) pathways[6,7,8,9,10]
We have demonstrated that PXS64 suppresses the deposition of fibronectin and collagen IV in human proximal tubular cells exposed to latent TGF-β1 for 48hours
Summary
Tubulointerstitial fibrosis is generally recognized as the final common pathway of chronic kidney disease (CKD) [1]. It is characterized by the accumulation of extracellular matrix (ECM), primarily consisting of collagen IV and fibronectin, which is considered a reliable prognostic. Convincing evidence from animals and clinical studies have clearly demonstrated that inhibiting the renin-angiotensin-aldosterone system (RAAS) pathways is effective in delaying progressive kidney disease [3]. TGF-β1 exists in abundance in its latent form bound to the Latency Associated Protein (LAP). Complete inhibition of TGF-β1 is irrelevant as TGF-β1 knockout animals exhibit a lethal phenotype at birth and treatment with a pan-antibody against TGF-β1 results in severe side effects, including fulminant sepsis[16]
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