Albumin in the mg/l-range activates NF-kappaB in renal proximal tubule-derived cell lines via tyrosine kinases and protein kinase C.
Albuminuria represents one of the most unfavourable diagnostic factors for the prognosis of nephropathies. We investigated albumin-induced NF-kappaB activation and the potential contribution of tyrosine kinase and protein kinase C. Therefore we exposed proximal tubule-derived human (IHKE-1), opossum (OK) and porcine (LLC-PK1) cell lines to serum albumin at concentrations of 10 - 500 mg/l. DNA-binding activity of NF-kappaB increased concentration-dependently in the presence of albumin. In OK and LLC-PK1 cells, NF-kappaB activity increased during the first 45 min and reached a plateau thereafter. In IHKE-1, cells NF-kappaB activity reached a plateau after 90 min with a maximum at 180 min exposure to albumin. The albumin-induced increase in NF-kappaB DNA-binding activity was inhibited by herbimycin A (tyrosine kinase inhibitor) and BIM (protein kinase C inhibitor). Reporter gene assays demonstrated that albumin stimulates NF-kappaB mediated reporter gene activation in LLC-PK1 cells, which was partially inhibited by herbimycin A and BIM. Our data indicate, that albumin exposure induces a rapid increase in NF-kappaB protein activity in renal proximal tubule cells of different species via a tyrosine kinase- and protein kinase C-dependent pathway, at concentrations occurring during mild glomerular injury.
Drumm
K
K
Institute of Physiology, University of Wuerzburg, Roentgenring 9, D-97070 Wuerzburg, Germany. karina.drumm@gmx.de
Gassner
B
B
Silbernagl
S
S
Gekle
M
M
D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D016227:Benzoquinones; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism*; D007700:Kinetics; D018374:LLC-PK1 Cells; D047029:Lactams, Macrocyclic; D008301:Maleimides / Q000494:pharmacology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009893:Opossums; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000494:pharmacology*; D013045:Species Specificity; D013552:Swine; D015533:Transcriptional Activation
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D007211:Indoles; D047029:Lactams, Macrocyclic; D008301:Maleimides; D016328:NF-kappa B; D011809:Quinones; D017828:Rifabutin; D012710:Serum Albumin, Bovine; C020754:herbimycin; D004247:DNA; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; C088060:bisindolylmaleimide