Nephrol Dial Transplant (2003) 18: 1493-1504
© 2003 European Renal Association-European Dialysis and Transplant Association
In situ activation pattern of Met docking site following renal injury and hypertrophy
1 Department of Pediatrics, Chaim Sheba Medical Center, Tel Hashomer, 2 Department of Human Microbiology, Sackler School of Medicine, Tel Aviv University, 3 Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute and 4 Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
Correspondence and offprint requests to: Dr Ilan Tsarfaty, Department of Human Microbiology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel 69978. Email: ilants{at}post.tau.ac.il
Background. Hepatocyte growth factor/scatter factor (HGF/SF) binds to its tyrosine kinase receptor, Met, thereby stimulating diverse cellular responses. The multifunctional docking site in the C-terminal domain mediates the signal of phosphorylated Met receptors to multiple transducers. The tyrosine at position 1356 of the Met docking site is crucial for cell motility and morphogenesis.
Methods. We examined the in situ distribution patterns of the Tyr1356-phosphorylated form of Met with a novel monoclonal antibody following renal injury and renal hypertrophy in rats. Sections of the kidney following either sham operation, transient ischaemia of one kidney or unilateral nephrectomy were analysed using indirect immunofluorescence staining and confocal laser scanning microscopy analysis of total Met protein levels and Tyr1356-phosphorylated Met (Met and pMet, respectively).
Results. At 6 h post-treatment, pMet increases in ischaemic kidneys compared with sham-operated kidneys, and these changes become substantial after 48 h in both medulla and cortex of ischaemic kidneys (P < 0.001). We also show significant up-regulation of Met predominantly in the medulla of ischaemic kidneys, 48 h following injury (P < 0.009). Inter-estingly, the stimulus for hypertrophy in the remnant kidney after uninephrectomy and the contra-lateral kidney during ischaemia is not accom-panied by significant up-regulation of Met or pMet staining compared with sham operation at both time points.
Conclusions. We demonstrate in this work, for the first time, in situ detection of tyrosine kinase growth factor receptor docking site activation during pathological processes in the kidney. Using this methodology, we show a significant increase in Met docking site activity in both renal medulla and cortex solely following stimulation by ischaemia and repair.
Keywords: HGF/SF; ischaemia; Met; signal transduction; tyrosine kinase docking site
B. Dekel and S. Biton contributed equally to this work.
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