Intracellular delivery of the p38 mitogen-activated protein kinase inhibitor SB202190 [4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H- imidazole] in renal tubular cells: A novel strategy to treat renal fibrosis

Jai Prakash, Maria Sandovici, Vinay Saluja, Marie Lacombe, Roel Q J Schaapveld, Martin H. De Borst, Harry Van Goor, Robert H. Henning, Johannes H. Proost, Frits Moolenaar, G. Kéri, Dirk K F Meijer, Klaas Poelstra, Robbert J. Kok

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Abstract

During renal injury, activation of p38 mitogen-activated protein kinase (MAPK) 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 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)- 5-(4-pyridyl)1H-imidazole] and the carrier lysozyme. First, we demonstrated that SB202190 inhibited the expression of albumin-induced proinflammatory (monocyte chemoattractant protein-1) and transforming growth factor (TGF)-β1-induced profibrotic (procollagen-Iα1) genes over 50% in renal tubular cells (normal rat kidney-52E). Next, we conjugated SB202190 via a carbamate linkage to lysozyme. However, this conjugate rapidly released the drug upon incubation in serum. Therefore, we applied a new platinum(II)-based linker approach, the so-called universal linkage system (ULS), which forms a coordinative bond with SB202190. The 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 intravenous injection. Treatment with SB202190-ULS-lysozyme inhibited TGF-β1-induced gene expression for procollagen-Iα1 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 α-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 MAPK inhibitor SB202190, which may be of use in the treatment of renal fibrosis.

Original languageEnglish
Pages (from-to)8-19
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume319
Issue number1
DOIs
Publication statusPublished - 2006

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p38 Mitogen-Activated Protein Kinases
Protein Kinase Inhibitors
Fibrosis
Kidney
Muramidase
Procollagen
Transforming Growth Factors
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole
Pharmaceutical Preparations
Carbamates
Muscle Proteins
Chemokine CCL2
Platinum
Reperfusion Injury
Serum
Intravenous Injections
Reperfusion
Smooth Muscle
Actins
Albumins

ASJC Scopus subject areas

  • Pharmacology

Cite this

Intracellular delivery of the p38 mitogen-activated protein kinase inhibitor SB202190 [4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H- imidazole] in renal tubular cells : A novel strategy to treat renal fibrosis. / Prakash, Jai; Sandovici, Maria; Saluja, Vinay; Lacombe, Marie; Schaapveld, Roel Q J; De Borst, Martin H.; Van Goor, Harry; Henning, Robert H.; Proost, Johannes H.; Moolenaar, Frits; Kéri, G.; Meijer, Dirk K F; Poelstra, Klaas; Kok, Robbert J.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 319, No. 1, 2006, p. 8-19.

Research output: Contribution to journalArticle

Prakash, Jai ; Sandovici, Maria ; Saluja, Vinay ; Lacombe, Marie ; Schaapveld, Roel Q J ; De Borst, Martin H. ; Van Goor, Harry ; Henning, Robert H. ; Proost, Johannes H. ; Moolenaar, Frits ; Kéri, G. ; Meijer, Dirk K F ; Poelstra, Klaas ; Kok, Robbert J. / Intracellular delivery of the p38 mitogen-activated protein kinase inhibitor SB202190 [4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H- imidazole] in renal tubular cells : A novel strategy to treat renal fibrosis. In: Journal of Pharmacology and Experimental Therapeutics. 2006 ; Vol. 319, No. 1. pp. 8-19.
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abstract = "During renal injury, activation of p38 mitogen-activated protein kinase (MAPK) 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 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)- 5-(4-pyridyl)1H-imidazole] and the carrier lysozyme. First, we demonstrated that SB202190 inhibited the expression of albumin-induced proinflammatory (monocyte chemoattractant protein-1) and transforming growth factor (TGF)-β1-induced profibrotic (procollagen-Iα1) genes over 50{\%} in renal tubular cells (normal rat kidney-52E). Next, we conjugated SB202190 via a carbamate linkage to lysozyme. However, this conjugate rapidly released the drug upon incubation in serum. Therefore, we applied a new platinum(II)-based linker approach, the so-called universal linkage system (ULS), which forms a coordinative bond with SB202190. The 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 intravenous injection. Treatment with SB202190-ULS-lysozyme inhibited TGF-β1-induced gene expression for procollagen-Iα1 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 α-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 MAPK inhibitor SB202190, which may be of use in the treatment of renal fibrosis.",
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AU - Prakash, Jai

AU - Sandovici, Maria

AU - Saluja, Vinay

AU - Lacombe, Marie

AU - Schaapveld, Roel Q J

AU - De Borst, Martin H.

AU - Van Goor, Harry

AU - Henning, Robert H.

AU - Proost, Johannes H.

AU - Moolenaar, Frits

AU - Kéri, G.

AU - Meijer, Dirk K F

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