Abstract
BackgroundCubilin is an endocytic receptor that is necessary for renal and intestinal absorption of a range of ligands. Endocytosis mediated by cubilin and its co-receptor megalin is the principal mechanism for proximal tubule reabsorption of proteins from the glomerular filtrate. Cubilin is also required for intestinal endocytosis of intrinsic factor-vitamin B12 complex. Despite its importance, little is known about the regulation of cubilin expression.ResultsHere we show that cubilin expression is under epigenetic regulation by at least two processes. The first process involves inactivation of expression of one of the cubilin alleles. This monoallelic expression state could not be transformed to biallelic by inhibiting DNA methylation or histone deacetylation. The second process involves transcriptional regulation of cubilin by peroxisome proliferator-activated receptor (PPAR) transcription factors that are themselves regulated by DNA methylation and histone deacetylation. This is supported by findings that inhibitors of DNA methylation and histone deacetylation, 5Aza and TSA, increase cubilin mRNA and protein in renal and intestinal cell lines. Not only was the expression of PPARα and γ inducible by 5Aza and TSA, but the positive effects of TSA and 5Aza on cubilin expression were also dependent on both increased PPAR transcription and activation. Additionally, 5Aza and TSA had similar effects on the expression of the cubilin co-receptor, megalin.ConclusionsTogether, these findings reveal that cubilin and megalin mRNA expression is under epigenetic control and thus point to new avenues for overcoming pathological suppression of these genes through targeting of epigenetic regulatory processes.
Highlights
Cubilin is an endocytic receptor that is necessary for renal and intestinal absorption of a range of ligands
Cubilin is expressed by the absorptive epithelia of tissues such as renal proximal convoluted tubules [5], ileum [6], and yolk sac [7], where it mediates the endocytosis of numerous ligands [1], in some cases acting in concert with another endocytic receptor, LRP-2/megalin [8]
Effects of TSA on cubilin in NRK and Caco-2 cells We evaluated the effects of the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), on cubilin mRNA expression in NRK and Caco-2 cells
Summary
Cubilin is an endocytic receptor that is necessary for renal and intestinal absorption of a range of ligands. Endocytosis mediated by cubilin and its co-receptor megalin is the principal mechanism for proximal tubule reabsorption of proteins from the glomerular filtrate. Cubilin is expressed by the absorptive epithelia of tissues such as renal proximal convoluted tubules [5], ileum [6], and yolk sac [7], where it mediates the endocytosis of numerous ligands [1], in some cases acting in concert with another endocytic receptor, LRP-2/megalin [8]. Mutations of the cubilin gene are the cause of Imerslund-Gräsbeck syndrome, known as selective vitamin B12 malabsorption with proteinuria [10]. Expression of megalin is regulated by histone acetylation and methylation and DNA methylation [16], but it is not yet known whether cubilin is regulated epigenetically in a similar manner
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