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
| Autor: | Roel Q. J. Schaapveld, György Kéri, Maria Sandovici, Robert H. Henning, Frits Moolenaar, Robbert J. Kok, Marie Lacombe, Martin H. de Borst, Jai Prakash, Klaas Poelstra, Johannes H. Proost, Vinay Saluja, Harry van Goor, Dirk K. F. Meijer |
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| Přispěvatelé: | Groningen University Institute for Drug Exploration (GUIDE), Nanomedicine & Drug Targeting, Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Vascular Ageing Programme (VAP), Nanotechnology and Biophysics in Medicine (NANOBIOMED), Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Organ Transplantation (GIOT), Translational Immunology Groningen (TRIGR) |
| Rok vydání: | 2006 |
| Předmět: |
Male
MAPK/ERK pathway Pyridines ALBUMIN Pharmacology Kidney p38 Mitogen-Activated Protein Kinases Nephrotoxicity Proinflammatory cytokine Kidney Tubules Proximal CISPLATIN Fibrosis INJURY medicine Renal fibrosis Animals Rats Wistar Protein kinase A Protein Kinase Inhibitors MAP KINASES PLATINUM NEPHROTOXICITY RECEPTOR business.industry Monocyte Imidazoles PATHWAYS Biological Transport COMPOUND medicine.disease Rats APOPTOSIS medicine.anatomical_structure Biochemistry Reperfusion Injury Molecular Medicine Muramidase business |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics, 319(1), 8-19. WILLIAMS & WILKINS |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.106.106054 |
| Popis: | 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)-beta 1-induced profibrotic (procollagen- I alpha 1) 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-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 MAPK inhibitor SB202190, which may be of use in the treatment of renal fibrosis. |
| Databáze: | OpenAIRE |
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