Focal segmental glomerulosclerosis (FSGS) is a frequent and severe glomerular disease characterized by destabilization of podocyte foot processes. We report that transgenic expression of the microRNA miR-193a in mice rapidly induces FSGS with extensive podocyte foot process effacement. Mechanistically, miR-193a inhibits the expression of the Wilms' tumor protein (WT1), a transcription factor and master regulator of podocyte differentiation and homeostasis. Decreased expression levels of WT1 lead to downregulation of its target genes PODXL (podocalyxin) and NPHS1 (nephrin), as well as several other genes crucial for the architecture of podocytes, initiating a catastrophic collapse of the entire podocyte-stabilizing system. We found upregulation of miR-193a in isolated glomeruli from individuals with FSGS compared to normal kidneys or individuals with other glomerular diseases. Thus, upregulation of miR-193a provides a new pathogenic mechanism for FSGS and is a potential therapeutic target.

The thyroid hormone receptor (TR) has been proposed to regulate expression of target genes in the absence of triiodothyronine (T3) through the recruitment of the corepressors, NCoR and SMRT. Thus, NCoR and SMRT may play an essential role in thyroid hormone action, although this has never been tested in vivo. To accomplish this, we developed mice that express in the liver a mutant NCoR protein (L-NCoR⌬ID) that cannot interact with the TR. L-NCoR⌬ID mice appear grossly normal, however, when made hypothyroid the repression of many positively regulated T 3-target genes is abrogated, demonstrating that NCoR plays a specific and sufficient role in repression by TR in the absence of T 3. Remarkably, in the euthyroid state, expression of many T 3-targets is also up-regulated in L-NCoR⌬ID mice, demonstrating that NCoR also determines the magnitude of the response to T 3 in euthyroid animals. Although positive T 3 targets were up-regulated in L-NCoR⌬ID mice in the hypo-and euthyroid state, there was little effect seen on negatively regulated T 3 target genes. Thus, NCoR is a specific regulator of T 3-action in vivo and mediates repression by the unliganded TR in hypothyroidism. Furthermore, NCoR appears to play a key role in determining the tissue-specific responses to similar levels of circulating T 3. Interestingly, NCoR recruitment to LXR is also impaired in this model, leading to activation of LXRtarget genes, further demonstrating that NCoR recruitment regulates multiple nuclear receptor signaling pathways.gene expression ͉ thyroid hormone receptor