TY - JOUR
T1 - Cell-specific delivery of a transforming growth factor-beta type I receptor kinase inhibitor to proximal tubular cells for the treatment of renal fibrosis
AU - Prakash, Jai
AU - De Borst, Martin H.
AU - Van Loenen-Weemaes, Annemiek M.
AU - Lacombe, Marie
AU - Opdam, Frank
AU - Van Goor, Harry
AU - Meijer, Dirk K.F.
AU - Moolenaar, Frits
AU - Poelstra, Klaas
AU - Kok, Robbert J.
PY - 2008/10/1
Y1 - 2008/10/1
N2 - Purpose. Activation of tubular epithelial cells by transforming growth factor-beta (TGF-β) plays an important role in the pathogenesis of renal tubulointerstitial fibrosis. We developed a renally accumulating conjugate of a TGF-β type-I receptor kinase inhibitor (TKI) and evaluated its efficacy in vitro and in vivo. Methods. TKI was conjugated to the protein Lysozyme (LZM) via a platinum-based linker. TKI-LZM was evaluated in human tubular cells (HK-2) for its anti-fibrotic activity. Plasma, kidney and urine drug levels after a single intravenous dose of TKI-LZM in rats were determined by HPLC or immunodetection. Anti-fibrotic effects of TKI-LZM were examined in the unilateral ureteral obstruction (UUO) model. Results. TKI-LZM conjugate was successfully synthesized at an 1:1 drug/carrier ratio, and inhibited TGF-β1-induced procollagen-1α1 gene expression in HK-2 cells. In vivo, TKI-LZM accumulated rapidly in tubular cells and provided a local depot for 3 days. Interestingly, a single dose of TKI-LZM inhibited the activation of tubular cells and fibroblasts in UUO rats and reduced renal inflammation. In contrast, free TKI at an equimolar (low) dosage exhibited little effects. Conclusions. Inhibition of TGF-beta signaling by local drug delivery is a promising antifibrotic strategy, and demonstrated the important role of tubular activation in renal fibrosis.
AB - Purpose. Activation of tubular epithelial cells by transforming growth factor-beta (TGF-β) plays an important role in the pathogenesis of renal tubulointerstitial fibrosis. We developed a renally accumulating conjugate of a TGF-β type-I receptor kinase inhibitor (TKI) and evaluated its efficacy in vitro and in vivo. Methods. TKI was conjugated to the protein Lysozyme (LZM) via a platinum-based linker. TKI-LZM was evaluated in human tubular cells (HK-2) for its anti-fibrotic activity. Plasma, kidney and urine drug levels after a single intravenous dose of TKI-LZM in rats were determined by HPLC or immunodetection. Anti-fibrotic effects of TKI-LZM were examined in the unilateral ureteral obstruction (UUO) model. Results. TKI-LZM conjugate was successfully synthesized at an 1:1 drug/carrier ratio, and inhibited TGF-β1-induced procollagen-1α1 gene expression in HK-2 cells. In vivo, TKI-LZM accumulated rapidly in tubular cells and provided a local depot for 3 days. Interestingly, a single dose of TKI-LZM inhibited the activation of tubular cells and fibroblasts in UUO rats and reduced renal inflammation. In contrast, free TKI at an equimolar (low) dosage exhibited little effects. Conclusions. Inhibition of TGF-beta signaling by local drug delivery is a promising antifibrotic strategy, and demonstrated the important role of tubular activation in renal fibrosis.
KW - Lysozyme
KW - Proximal tubular cells
KW - Transforming growth factor
KW - Tyrosine kinase inhibitor
KW - Unilateral ureteral obstruction
UR - http://www.scopus.com/inward/record.url?scp=51649106180&partnerID=8YFLogxK
U2 - 10.1007/s11095-007-9515-x
DO - 10.1007/s11095-007-9515-x
M3 - Article
C2 - 18183478
AN - SCOPUS:51649106180
SN - 0724-8741
VL - 25
SP - 2427
EP - 2439
JO - Pharmaceutical research
JF - Pharmaceutical research
IS - 10
ER -
