Abstract
Glomerular podocytes are highly differentiated epithelial cells that are key components of the kidney filtration units. Podocyte damage or loss is the hallmark of nephritic diseases characterized by severe proteinuria. Recent studies implicate that hormones including glucocorticoids (ligand for glucocorticoid receptor) and vitamin D3 (ligand for vitamin D receptor) protect or promote repair of podocytes from injury. In order to elucidate the mechanisms underlying hormone-mediated podocyte-protecting activity from injury, we carried out microarray gene expression studies to identify the target genes and corresponding pathways in response to these hormones during podocyte differentiation. We used immortalized human cultured podocytes (HPCs) as a model system and carried out in vitro differentiation assays followed by dexamethasone (Dex) or vitamin D3 (VD3) treatment. Upon the induction of differentiation, multiple functional categories including cell cycle, organelle dynamics, mitochondrion, apoptosis and cytoskeleton organization were among the most significantly affected. Interestingly, while Dex and VD3 are capable of protecting podocytes from injury, they only share limited target genes and affected pathways. Compared to VD3 treatment, Dex had a broader and greater impact on gene expression profiles. In-depth analyses of Dex altered genes indicate that Dex crosstalks with a broad spectrum of signaling pathways, of which inflammatory responses, cell migration, angiogenesis, NF-κB and TGFβ pathways are predominantly altered. Together, our study provides new information and identifies several new avenues for future investigation of hormone signaling in podocytes.
Highlights
Podocytes are highly differentiated kidney cells that produce the slit diaphragm, a key component of the renal glomerulus filtration barrier, responsible for removing toxins and metabolic waste while retaining leukocytes and larger proteins in the bloodstream
We first examined the expression levels of GRa and VDR by qRTPCR using two pairs of primers for both GRa and VDR. We found that both GRa and VDR were expressed in human podocytes (HPCs), but that GRa mRNA levels were expressed 30-fold higher than VDR
To examine the optimal hormonal effects during the differentiation process, two days after induction, HPCs were treated with vehicle, 100 nM vitamin D3 (VD3) or 100 nM dexamethasone (Dex) for 3 more days (Figure 1C)
Summary
Podocytes are highly differentiated kidney cells that produce the slit diaphragm, a key component of the renal glomerulus filtration barrier, responsible for removing toxins and metabolic waste while retaining leukocytes and larger proteins in the bloodstream. Critical to podocyte development and differentiation are events mediated by numerous cell permeable hormones [1]. These small lipopholic molecules such as steroids, fatty acids, prostaglandins and vitamin metabolites control many aspects of animal development through binding to a family of intracellular receptors, the nuclear receptors (NRs). The mechanism underlying the ability of these hormones to protect podocytes and kidney function is an important issue for patient treatment that remains poorly understood. This is partly due to the limited knowledge of the target genes and affected pathways controlled by these hormones. Glucocorticoid treatment studies in animals and patients cannot separate direct versus indirect effects, more comprehensive studies should provide valuable information on the direct effects on the renal cells, the intended target of the therapy
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