title: Acute endotoxemia in mice induces downregulation of megalin and cubilin in the kidney.
abstract: Severe sepsis is often accompanied by acute renal failure with renal tubular dysfunction. Albuminuria is a common finding in septic patients and we studied whether it was due to an impairment of proximal tubular endocytosis of filtered albumin. We studied the regulation of megalin and cubilin, the two critical multiligand receptors responsible for albumin absorption, during severe experimental endotoxemia. Lipopolysaccharide (LPS) caused a time- and dose-dependent suppression of megalin and cubilin expression that was paralleled by a decrease in plasma albumin levels and an increase in the urine concentration of albumin in mice. Incubation of rat renal cortical slices with LPS also reduced the mRNA expression of megalin and cubilin. Further, LPS suppressed megalin and cubilin mRNA expression in murine primary proximal tubule cells and decreased the uptake of FITC albumin in these cells. In addition, the increase in urine levels of albumin in response to ischemia/reperfusion-induced acute renal failure was paralleled by a decrease in the expression of megalin and cubilin. Thus, our data indicate that the expression of megalin and cubilin is decreased during experimental endotoxemia and in response to renal ischemia/reperfusion injury. This downregulation may contribute, in part, to an increase in urine levels of albumin during acute renal failure.
authors.affiliation: Institute of Physiology, University of Regensburg, Regensburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schreiber
authors.forename: Franziska
authors.initials: F
authors.lastname: Theilig
authors.forename: Frank
authors.initials: F
authors.lastname: Schweda
authors.forename: Klaus
authors.initials: K
authors.lastname: Höcherl
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D000419:Albuminuria / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology / Q000652:urine; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D004705:Endocytosis; D019446:Endotoxemia / Q000097:blood / Q000139:chemically induced / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D007671:Kidney Concentrating Ability; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000503:physiopathology; D008070:Lipopolysaccharides; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000150:complications / Q000235:genetics / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism; D013997:Time Factors
chemical_list: D015415:Biomarkers; C518288:FITC-albumin; D008070:Lipopolysaccharides; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D012709:Serum Albumin; C029486:intrinsic factor-cobalamin receptor; C440499:lipopolysaccharide, Escherichia coli O111 B4; D016650:Fluorescein-5-isothiocyanate