Abstract
BackgroundChronic exposure to low cadmium (Cd) levels produces urinary excretion of low molecular weight proteins, which is considered the critical effect of Cd exposure. However, the mechanisms involved in Cd-induced proteinuria are not entirely clear. Therefore, the present study was designed to evaluate the possible role of megalin and cubilin (important endocytic receptors in proximal tubule cells) and angiotensin II type 1 (AT1) receptor on Cd-induced microalbuminuria.MethodsFour groups of female Wistar rats were studied. Control (CT) group, vehicle-treated rats; LOS group, rats treated with losartan (an AT1 antagonist) from weeks 5 to 8 (10 mg/kg/day by gavage); Cd group, rats subchronically exposed to Cd (3 mg/kg/day by gavage) during 8 weeks, and Cd + LOS group, rats treated with Cd for 8 weeks and LOS from weeks 5–8. Kidney Cd content, glomerular function (evaluated by creatinine clearance and plasma creatinine), kidney injury and tubular function (evaluated by Kim-1 expression, urinary excretion of N-acetyl-β-D-glucosaminidase (NAG) and glucose, and microalbuminuria), oxidative stress (measured by lipid peroxidation and NAD(P)H oxidase activity), mRNA levels of megalin, expressions of megalin and cubilin (by confocal microscopy) and AT1 receptor (by Western blot), were measured in the different experimental groups. Data were analyzed by one-way ANOVA or Kruskal-Wallis test using GraphPad Prism 5 software (Version 5.00). P < 0.05 was considered statistically significant.ResultsAdministration of Cd (Cd and Cd + LOS groups) increased renal Cd content. LOS-treatment decreased Cd-induced microalbuminuria without changes in: plasma creatinine, creatinine clearance, urinary NAG and glucose, oxidative stress, mRNA levels of megalin and cubilin, neither protein expression of megalin nor AT1 receptor, in the different experimental groups studied. However, Cd exposure did induce the expression of the tubular injury marker Kim-1 and decreased cubilin protein levels in proximal tubule cells whereas LOS-treatment restored cubilin levels and suppressed Kim-1 expression.ConclusionLOS treatment decreased microalbuminuria induced by Cd apparently through a cubilin receptor-dependent mechanism but independent of megalin.
Highlights
Chronic exposure to low cadmium (Cd) levels produces urinary excretion of low molecular weight proteins, which is considered the critical effect of Cd exposure
Megalin is a multiligand receptor with a large NH2-terminal extracellular domain rich in cysteine, a single transmembrane domain and a COOH-terminal short cytoplasmic domain with NPXY motifs that are responsible for internalization mediated by clathrin [22,23,24]
We evaluated the role of the megalin-cubilin complex and angiotensin II type 1 (AT1) receptor on tubular endocytosis of albumin during a subchronic exposure to Cd in rats
Summary
Chronic exposure to low cadmium (Cd) levels produces urinary excretion of low molecular weight proteins, which is considered the critical effect of Cd exposure. A decrease in the expression of megalin receptor favors the presence of proteins into urine (as captesin B, RPB and albumin) [21] and cubilin deficiency leads to an increase in albumin excretion [26]. Endocytosis along the proximal tubule is regulated by different factors, including angiotensin II (Ang II), an active vasopeptide of the renin-angiotensin system (RAS). It has been suggested that Ang II can downregulate megalin and the treatment with RAS inhibitors or AT1 receptor blockers decreases proteinuria and protects kidney function independent of the effect of drugs on blood pressure [29,30]. We evaluated the role of the megalin-cubilin complex and AT1 receptor on tubular endocytosis of albumin during a subchronic exposure to Cd in rats
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