Activation of mitogenic pathways by albumin in kidney proximal tubule epithelial cells: implications for the pathophysiology of proteinuric states.
Albumin is filtered into the proximal tubule in large quantities in nephrotic states. It has been proposed that this protein may have a toxic effect on tubular epithelial cells and may be responsible for the initiation of interstitial inflammation and scarring. The mitogenic effect of recombinant human albumin in wild-type opossum kidney cells and in similar cells transfected with a dominant negative p85 subunit (deltap85) of phopshatidylinositide 3-kinase (PI 3-kinase) has been studied. This study demonstrates that recombinant human albumin stimulates proliferation of opossum kidney cells in culture. This effect is mediated via PI 3-kinase, and is inhibited by wortmannin and deltap85 expression. Albumin stimulates PI 3-kinase activity in opossum kidney cells as determined by three different experimental procedures. Recombinant albumin also stimulates pp70(s6) kinase activity in a kinase cascade downstream of PI 3-kinase. Activity of pp70(s6) kinase is essential for albumin-induced proliferation of opossum kidney cells. It is proposed that this mitogenic pathway may have a critical role in proximal tubular homeostasis and pathophysiology of proteinuric states.
Department of Cell Physiology and Pharmacology, Leicester University School of Medicine, United Kingdom.
R
R
Dixon
N J
NJ
Brunskill
D000418:Albumins / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology; D008938:Mitosis / Q000187:drug effects*; D009893:Opossums; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011507:Proteinuria / Q000473:pathology* / Q000503:physiopathology*; D011994:Recombinant Proteins / Q000494:pharmacology; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D014162:Transfection
D000418:Albumins; D011994:Recombinant Proteins; D019869:Phosphatidylinositol 3-Kinases; D019893:Ribosomal Protein S6 Kinases