Adriamycin alters glomerular endothelium to induce proteinuria.
The pathophysiology underlying the nephrotic syndrome is becoming clear for several inherited podocytopathies; the mechanisms of injury that lead to the acquired forms of this disease are not well understood. We explored these mechanisms using the mouse model of adriamycin-induced proteinuria.We estimated the fractional clearances for FITC-Ficolls, albumin, and neutral albumin in cooled, isolated,perfused kidneys (cIPK) in situ. Treatment with adriamycin led to a significant increase in the fractional clearance of albumin and of Ficoll with radii larger than 20 A. Neutral albumin (33.4 A) and similarly sized Ficoll behaved similarly to each other. In addition, adriamycin led to a significant loss of charge density and size selectivity of the glomerular barrier. The thickness of the glomerular endothelial surface layer(i.e., or the glycocalyx) in adriamycin-treated animals was only 20% of that in normal animals. Finally,several proteoglycans were downregulated in isolated glomeruli. In summary, adriamycin thins the glomerular glycocalyx, perhaps by downregulating proteoglycan synthesis, and alters glomerular charge- and size selectivity. These data suggest that the glomerular endothelium may play a role in the pathogenesis of proteinuric renal diseases.
Jeansson
Marie
M
The Renal Center/Wallenberg Laboratory, Institute of Internal Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Björck
Karin
K
Tenstad
Olav
O
Haraldsson
Börje
B
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D004317:Doxorubicin / Q000633:toxicity*; D004727:Endothelium / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011507:Proteinuria / Q000139:chemically induced*; D012333:RNA, Messenger / Q000032:analysis; D053675:Versicans / Q000032:analysis / Q000235:genetics
D000903:Antibiotics, Antineoplastic; D012333:RNA, Messenger; C508323:Vcan protein, mouse; D053675:Versicans; D004317:Doxorubicin