Acute endotoxemia in mice induces downregulation of megalin and cubilin in the kidney

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.     

Immunological Studies of Patients with Down's Syndrome

Abstract. Recurrent diarrhoea and weight loss in many adult patients with Down's syndrome (DS), initiated a search for malabsorption based on determination of serum IgG and IgA antibody levels to dietary antigens. The results were compared with measurements of autoantibodies and serum zinc levels. DS patients had increased IgG and IgA activities to gluten proteins, casein and ovalbumin compared with an age- and sex-matched group of other mentally retarded patients in the same institution. Intestinal biopsy was performed in six of the 38 patients; one had total and one partial villous atrophy. Serum zinc was significantly lower in DS patients (median 14.7 μmol/l, range 5.5–20 μmol/l) than in the controls (median 16.4 μmol/l, range 12.7–19.5 μmol/l). DS patients with increased IgA activity to gluten weighed less and had lower concentrations of zinc in serum than DS patients with normal IgA activity. Twenty-eight per cent of the DS patients had autoantibodies to the thyroid gland. Our results suggest intestinal malfunction in DS, perhaps related to a defect of immune regulation caused by reduced levels of zinc in serum.