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.
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)-beta1-induced profibrotic (procollagen-Ialpha1) 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-beta1-induced gene expression for procollagen-Ialpha1 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.
Prakash
Jai
J
Department of Pharmaceutics, Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands.
Sandovici
Maria
M
Saluja
Vinay
V
Lacombe
Marie
M
Schaapveld
Roel Q J
RQ
de Borst
Martin H
MH
van Goor
Harry
H
Henning
Robert H
RH
Proost
Johannes H
JH
Moolenaar
Frits
F
Këri
György
G
Meijer
Dirk K F
DK
Poelstra
Klaas
K
Kok
Robbert J
RJ
D000818:Animals; D001692:Biological Transport; D002945:Cisplatin / Q000633:toxicity; D005355:Fibrosis; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007668:Kidney / Q000098:blood supply / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009113:Muramidase / Q000008:administration & dosage / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; D009113:Muramidase; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; D002945:Cisplatin