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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 28, 2006; DOI: 10.1124/jpet.106.106054

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Received for publication April 12, 2006.
Revised June 22, 2006.
Accepted for publication June 27, 2006.

Intracellular Delivery of the P38 MAPK Inhibitor SB202190 in Renal Tubular Cells: a Novel Strategy to Treat Renal Fibrosis

Jai Prakash 1*, Maria Sandovici 1, Vinay Saluja 1, Marie Lacombe 2, Roel Q.J. Schaapveld 2, Martin de Borst 1, Harry van Goor 1, Robert H. Henning 1, Johannes H. Proost 1, Frits Moolenaar 1, Gyorgy Keri 3, Dirk K.F. Meijer 1, Klaas Poelstra 1, Robbert J. Kok 1

1 Groningen University Institute for Drug Exploration 2 Kreatech Biotechnology 3 Vichem Chemie Research Ltd.

* Address correspondence to: E-mail: j.prakash{at}rug.nl

Abstract

During renal injury, activation of p38 MAPkinase in proximal tubular cells plays an important role in the inflammatory events that eventually lead to renal fibrosis. We hypothesized that local inhibition of p38 within these cells may be an interesting approach for the treatment of renal fibrosis. To effectuate this, we developed a renal specific conjugate of the p38 inhibitor SB202190 and the carrier lysozyme. First, we demonstrated that SB202190 inhibited the expression of albumin-induced proinflammatory (MCP-1) and TGF-{beta}1- induced profibrotic (procollagen-I{alpha}1) genes over 50% in renal tubular cells (NRK-52E). Next, we conjugated SB202190 via a carbamate linkage to lysozyme. However, this conjugate rapidly released the drug upon incubation in serum. We therefore applied a new platinum (II) based linker approach, so-called Universal Linkage System (ULSTM), which forms a coordinative bond with SB202190. SB202190-ULS-lysozyme remained stable in serum but released the drug in kidney homogenates. SB202190-ULS-lysozyme accumulated efficiently in renal tubular cells and provided a local drug reservoir during a period of 3 days after a single i.v. injection. Treatment with SB202190-ULS-lysozyme inhibited TGF-{beta}1-induced gene expression for procollagen-I{alpha}1 by 64% in HK-2 cells. Lastly, we evaluated the efficacy of a single dose of the conjugate in the unilateral renal ischemia-reperfusion rat model. A reduction of intrarenal p38 phosphorylation and alpha-smooth muscle actin protein expression was observed 4 days after the ischemia-reperfusion injury. In conclusion, we have developed a novel strategy for local delivery of the p38 MAPkinase inhibitor SB202190 which may be of use in the treatment of renal fibrosis.


Key words: Renal drug targeting, lysozyme, p38 mitogen-activated protein kinase, renal fibrosis, renal tubular cells, transforming growth factor-beta


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