Nuclear hormone receptors in podocytes

Abstract

Nuclear receptors are a family of ligand-activated, DNA sequence-specific transcription factors that regulate various aspects of animal development, cell proliferation, differentiation, and homeostasis. The physiological roles of nuclear receptors and their ligands have been intensively studied in cancer and metabolic syndrome. However, their role in kidney diseases is still evolving, despite their ligands being used clinically to treat renal diseases for decades. This review will discuss the progress of our understanding of the role of nuclear receptors and their ligands in kidney physiology with emphasis on their roles in treating glomerular disorders and podocyte injury repair responses.

Figure 1

A schematic representation of a nuclear receptor: Nuclear receptors consist of four domains (A-F): The N-terminal ligand-independent transactivation domain (A/B), the DNA binding domain (C), hinge region (D), and C-terminal E/F domain including LBD and ligand dependent transactivation domain. Functions of specific domains are indicated in the text boxes.

Figure 2

Ligand-dependent conformational change and transactivation of a nuclear receptor. In the absence of ligand, nuclear receptors are associated with corepressor complexes such as SMRT, HDACs and histone methyltransferases (HMTs) and inhibit transcription by keeping the chromatin tightly bound around the promoter. Ligand binding induces a conformational change in the structure of nuclear receptors which exchanges the corepressors with coactivators. The coactivators including CBP/p300, PCAF and SRCs loosen chromatin by acetylating histone tails. Acetylation of histone tails opens up the chromatin which in turn allows basal transcriptional machinery to target promoters.

Figure 3

Mechanisms underlying NR-mediated transrepression. A, Liganded GR binds to Fos subunit of activator protein 1 (AP-1) and represses a subset of AP-1-dependent genes through GR interacting protein 1(GRIP-1). B. Liganded GR binds to p65 subunit of nuclear factor-κB (NF-κB) and prevents the binding of interferon regulatory factor 3 (IRF3) or positive transcription elongation factor b (P-TEFb) to the promoter of some NF-κB target genes. C, Liganded GR binds to Fos subunit of AP-1 and represses a subset of AP-1 dependent genes through nuclear thyroid receptor interactor 6 (NTRIP6). D, Liganded PPARγ (or LXR) is posttranslationally modified by Sumo1 (or Sumo2) conjugation, which facilitates an interaction with nuclear receptor corepressor (NCoR) complex to inhibit the recruitment of ubiquitin-conjugating enzymes and 19S proteasome components (not shown) required for the degradation of NCoR. Transcription start site is shown as +1. GTF refers to the general transcription factors. Pol II refers to RNA polymerase II. This figure is adopted from Glass and Saijo (42).

Figure 4

The structure of podocyte. The glomerular capillary wall consists of a fenestrated endothelium, a basement membrane and podocyte foot processes. The foot processes form the filtration slits and are spanned by slit diaphragms. The slit diaphragm is composed of the extracellular domains of a number of unique transmembrane proteins such as Nephrin, Neph-1, P-cadherins and FAT.