Cell-specific delivery of a transforming growth factor-beta type I receptor kinase inhibitor to proximal tubular cells for the treatment of renal fibrosis

Prakash, J., de Borst, M. H., van Loenen - Weemaes, A. M., Lacombe, M., Opdam, F., van Goor, H., Meijer, D. K. F., Moolenaar, F., Poelstra, K. & Kok, R. J., Oct-2008, In : Pharmaceutical Research. 25, 10, p. 2427-2439 13 p.

Research output: Contribution to journalArticleAcademicpeer-review

Purpose. Activation of tubular epithelial cells by transforming growth factor-beta (TGF-beta) plays an important role in the pathogenesis of renal tubulointerstitial fibrosis. We developed a renally accumulating conjugate of a TGF-beta 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-beta 1-induced procollagen-1 alpha 1 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.

Original languageEnglish
Pages (from-to)2427-2439
Number of pages13
JournalPharmaceutical Research
Issue number10
Publication statusPublished - Oct-2008


  • lysozyme, proximal tubular cells, transforming growth factor, tyrosine kinase inhibitor, unilateral ureteral obstruction, UNILATERAL URETERAL OBSTRUCTION, PROGRESSIVE FIBROSIS, ALK5 INHIBITOR, KIDNEY, ACCUMULATION, NEPHROPATHY, EXPRESSION, CISPLATIN, PLATINUM, BLOCKADE

ID: 4775156