Retinoic acid receptor responder1 promotes development of glomerular diseases via the Nuclear Factor-κB signaling pathway.

Nephrin, a crucial component of the slit diaphragm, is downregulated in proteinuric glomerular diseases including glomerulonephritis. We previously reported that 1) expression of nephrin in cultured podocytes is reinforced by retinoic acid (RA) and 1,25-dihydroxyvitamin D3, 2) these effects are mediated by retinoic acid receptor (RAR) and vitamin D receptor (VDR), and 3) basal and inducible expression of nephrin is downregulated by TNF-α. In the present investigation, we identified that TNF-α selectively represses activity of RAR but not VDR. To elucidate mechanisms underlying this observation, we tested involvement of downstream targets for TNF-α: nuclear factor-κB (NF-κB), mitogen-activated protein (MAP) kinases, phosphatidylinositol 3-kinase (PI3K)-Akt, and cAMP-protein kinase A (PKA). TNF-α caused activation of NF-κB, MAP kinases, and PI3K-Akt in podocytes, whereas blockade of these molecules did not affect inhibition of RAR by TNF-α. In contrast, TNF-α depressed activity of cAMP-PKA, and blockade of PKA inhibited basal and RA-induced activation of RAR. Furthermore, activity of RAR was significantly upregulated by cAMP, and the suppressive effect of TNF-α on RAR was reversed by cAMP-elevating agents. These results suggest that 1) expression of nephrin in podocytes is regulated by the cAMP-RAR pathway and 2) suppression of nephrin by TNF-α is caused, at least in part, through selective inhibition of this pathway.

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Hepatocyte nuclear factor-6 stimulates transcription of the alpha-fetoprotein gene and synergizes with the retinoic-acid-receptor-related orphan receptor alpha-4

Biochemical Journal ◽

10.1042/bj20021229 ◽

2003 ◽

Vol 369 (3) ◽

pp. 583-591 ◽

Cited By ~ 7

Author(s):

Habib NACER-CHERIF ◽

Brigitte BOIS-JOYEUX ◽

Guy G. ROUSSEAU ◽

Frédéric P. LEMAIGRE ◽

Jean-Louis DANAN

Keyword(s):

Retinoic Acid ◽

Retinoic Acid Receptor ◽

Orphan Receptor ◽

Nuclear Factor ◽

Hepatocyte Nuclear Factor ◽

Acid Receptor ◽

Splicing Isoforms ◽

Liver Gene ◽

A Site ◽

Putative Binding Site

The rat α-fetoprotein (afp) gene is controlled by three enhancers whose function depends on their interaction with liver-enriched transcription factors. The afp enhancer III, located at −6kb, is composed of three regions that act in synergy. Two of these regions, called s1 and s2, contain a putative binding site for hepatocyte nuclear factor-6 (HNF-6). This factor is the prototype of the ONECUT family of cut-homoeodomain proteins and is a known regulator of liver gene expression in adults and during development. We show here that the two splicing isoforms of HNF-6 bind to a site in the s1 region and in the s2 region. The core sequence of the s1 site corresponds to none of the known HNF-6 binding sites. Nevertheless, the binding properties of the s1 site are identical with those of the s2 site and of previously characterized HNF-6 binding sequences. The HNF-6 consensus should therefore be rewritten as DRRTCVATND. Binding of HNF-6 to the s1 and s2 sites requires both the cut and the homoeo domains, is co-operative and induces DNA bending. HNF-6 strongly stimulates the activity of the afp enhancer III in transient transfection experiments. This effect requires the stereo-specific alignment of the two HNF-6 sites. Moreover, HNF-6 stimulates the enhancer in synergy with the retinoic-acid-receptor-related orphan receptor α (RORα), which binds to a neighbouring site in the s1 region. Thus expression of the afp gene requires functional interactions between HNF-6 molecules and between HNF-6 and RORα.

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