Expression profiling confirms the role of endocytic receptor megalin in renal vitamin D3 metabolism

Abstract

The endocytic receptor megalin constitutes the major pathway for clearance of low-molecular weight plasma proteins from the glomerular filtrate into the renal proximal tubules. Furthermore, the receptor has been implicated in a number of other functions in the kidney including uptake and activation of 25-(OH) vitamin D3, calcium and sodium reabsorption as well as signal transduction. We used genome-wide expression profiling by microarray technology to detect changes in the gene expression pattern in megalin knockout mouse kidneys and to uncover some of the renal pathways affected by megalin deficiency. Alterations were identified in several (patho)physiologic processes in megalin-deficient kidneys including the renal vitamin D metabolism, transforming growth factor (TGF)-beta1 signal transduction, lipid transport and heavy metal detoxification. Most importantly, changes were detected in the mRNA levels of 25-(OH) vitamin D-24-hydroxylase and 25-(OH) vitamin D-1alpha-hydroxylase as well as strong up-regulation of TGF-beta1 target genes. Both findings indicate plasma vitamin D deficiency and lack of vitamin D signaling in renal tissues. Expression profiling confirms a crucial role for megalin in renal vitamin D metabolism.