Retinoids in nephrology: Promises and pitfalls

Xu, Qihe; Lucio-Cazaña, Javier; Kitamura, Masanori; Ruan, Xiongzhong; Fine, Leon G.; Norman, Jill T.

doi:10.1111/j.1523-1755.2004.66002.x

Cited by 64 publications

(60 citation statements)

References 93 publications

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“…Although receptor-independent effects of retinoids have been described, most studies have shown that RAR and/or RXR play a role in retinoid-induced cellular effects through either genomic or nongenomic pathways (18,24,26). It was surprising that RAR␣, which is suppressed in HIV-infected cells, still played a critical role in atRA's effects on podocyte phenotype as supported by our data using the RAR␣ agonist and antagonist.…”

Section: Rar␣ Mediates the Effects Of Atra On Hiv-infected Podocytessupporting

confidence: 70%

“…RAR are expressed in many tissues, including the kidney (18). They affect gene transcription either directly by binding to the RA-response elements of a pro-moter region (18,19) or indirectly by modulating transcription factors such as activator-protein 1 (20,21) or NF-B (22). Activation of cytosolic signaling molecules by retinoids also has been reported as an important pathway to induce leukemia cell differentiation (23).…”

mentioning

confidence: 99%

“…All-trans-RA (atRA) binds and activates the RAR (RAR ␣, ␤, and ␥), whereas 9-cis RA binds and activates both the RAR and the RXR (RXR ␣, ␤, and ␥) (17). RAR are expressed in many tissues, including the kidney (18). They affect gene transcription either directly by binding to the RA-response elements of a pro-moter region (18,19) or indirectly by modulating transcription factors such as activator-protein 1 (20,21) or NF-B (22).…”

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confidence: 99%

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Retinoic Acid Inhibits HIV-1–Induced Podocyte Proliferation through the cAMP Pathway

He¹,

Lü²,

Fleet³

et al. 2007

Journal of the American Society of Nephrology

102

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HIV-associated nephropathy is characterized by renal podocyte proliferation and dedifferentiation. This study found that all-trans retinoic acid (atRA) reverses the effects of HIV-1 infection in podocytes. Treatment with atRA reduced cell proliferation rate by causing G1 arrest and restored the expression of the differentiation markers (synaptopodin, nephrin, podocin, and WT-1) in HIV-1-infected podocytes. It is interesting that both atRA and 9-cis RA increased intracellular cAMP levels in podocytes. Podocytes expressed most isoforms of retinoic acid receptors (RAR) and retinoid X receptors (RXR) with the exception of RXR␥. RAR␣ antagonists blocked atRA-induced cAMP production and its antiproliferative and prodifferentiation effects on podocytes, suggesting that RAR␣ is required. For determination of the effect of increased intracellular cAMP on HIV-infected podocytes, cells were stimulated with either forskolin or 8-bromo-cAMP. Both compounds inhibited cell proliferation significantly and restored synaptopodin expression in HIV-infected podocytes. The effects of atRA were abolished by Rp-cAMP, an inhibitor of the cAMP/protein kinase A pathway and were enhanced by rolipram, an inhibitor of phosphodiesterase 4, suggesting that the antiproliferative and prodifferentiation effects of atRA on HIV-infected podocytes are cAMP dependent. Furthermore, both atRA and forskolin suppressed HIV-induced mitogen-activated protein kinase 1 and 2 and Stat3 phosphorylation. In vivo, atRA reduced proteinuria, cell proliferation, and glomerulosclerosis in HIV-1-transgenic mice. These findings suggest that atRA reverses the abnormal phenotype in HIV-1-infected podocytes by stimulating RAR␣-mediated intracellular cAMP production. These results demonstrate the mechanism by which atRA reverses the proliferation of podocytes that is induced by HIV-1.

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Section: Rar␣ Mediates the Effects Of Atra On Hiv-infected Podocytessupporting

confidence: 70%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Retinoic Acid Inhibits HIV-1–Induced Podocyte Proliferation through the cAMP Pathway

He¹,

Lü²,

Fleet³

et al. 2007

Journal of the American Society of Nephrology

102

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“…Their effect is mediated by either directly binding to retinoic acid response elements or indirectly, by regulating other transcription factors such as NK-jB or AP-1 (reviewed in (96)). Treatment with isotretinoin (13-cis RA) ameliorated rat antiThy 1.1 glomerulonephritis, with a reduction in TGFb gene expression (97).…”

Section: Disrupting Matrix Accumulationmentioning

confidence: 99%

Therapeutic Targets in the Treatment of Allograft Fibrosis

Mannon

2006

American Journal of Transplantation

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The dramatic improvements in short-term graft survival and acute rejection rates could only have been dreamed of 20 years ago. Late graft loss following kidney transplantation is now the critical issue of this decade. Frequently, graft loss is associated with the development of tubular atrophy and interstitial fibrosis within the kidney (i.e. chronic allograft nephropathy; CAN). Major treatment strategies in this disorder are non-specific and the focus of intervention has been on limiting injurious events. Following graft injury is a fibrogenesis phase featuring both proliferative and infiltrative responses mediated by chemokines, cytokines and growth factors. In particular, TGFb has been strongly implicated in the pathogenesis of chronic injury and epithelial-mesenchymal transformation (EMT) may be part of this process. The cascade of events results in matrix accumulation, due to either increased production and/or reduced degradation of matrix. Recent investigations into the pathogenesis of tissue fibrosis have suggested a number of new strategies to ameliorate matrix synthesis. While the majority of therapies have focused on TGFb , this may not be an ideal maneuver in transplant settings and alternative targets identified in other fibrotic diseases will be discussed. Attacking graft fibrosis should be a new focus in organ transplantation.

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“…After binding of ATRA to RAR, RAR forms homodimers or heterodimers with RXR, and the resultant complexes exert biological effects via binding to the retinoic acid response element (RARE) (37). Three putative RAREs are present in the regulatory region of the human nephrin gene (28).…”

mentioning

confidence: 99%

Suppression of nephrin expression by TNF-α via interfering with the cAMP-retinoic acid receptor pathway

Saito

Okamura

Nakajima

et al. 2010

American Journal of Physiology-Renal Physiology

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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-␣. In the present investigation, we identified that TNF-␣ selectively represses activity of RAR but not VDR. To elucidate mechanisms underlying this observation, we tested involvement of downstream targets for TNF-␣: nuclear factor-B (NF-B), mitogen-activated protein (MAP) kinases, phosphatidylinositol 3-kinase (PI3K)-Akt, and cAMP-protein kinase A (PKA). TNF-␣ caused activation of NF-B, MAP kinases, and PI3K-Akt in podocytes, whereas blockade of these molecules did not affect inhibition of RAR by TNF-␣. In contrast, TNF-␣ 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-␣ 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-␣ is caused, at least in part, through selective inhibition of this pathway.tumor necrosis factor-␣; protein kinase A NEPHRIN, a podocyte-specific protein, is a key regulator that maintains normal structure and function of the slit diaphragm in the glomerulus (26). Loss of nephrin fails to form functional complexes in the slit membrane, resulting in dysfunction of the filtration barrier. In Finnish-type congenital nephrotic syndrome, massive proteinuria is caused by mutation of the nephrin gene (14). Similarly, disruption of the nephrin gene in mice results in abnormal foot process formation in podocytes and consequent nephrosis (21,22). Previous reports showed that the level of nephrin decreases in several proteinuric glomerular diseases including glomerulonephritis (9, 10, 15). However, information is limited regarding mechanisms underlying the downregulation of nephrin under pathological conditions.Cultured podocytes easily lose expression of nephrin in vitro. We previously reported (31, 38) that physiological ligands of nuclear receptors including all-trans-retinoic acid (ATRA) and 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] allow podocytes to maintain expression of nephrin in culture at both mRNA and protein levels. We also identified recently (19) that the nephrin gene promoter is activated by ATRA and 1,25(OH) 2 D 3 , which is mediated by the retinoic acid (RA) receptor (RAR) and the vitamin D receptor (VDR) but not the retinoid X receptor (RXR). On the other hand, activity of the nephrin gene promoter is downregulated by bystander macrophages as well as macrophage-derived cytokines including tumor necrosis factor-␣ (TNF-␣) and IL-1␤. This repression is reversible and obs...

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Retinoids in nephrology: Promises and pitfalls

Abstract: Retinoids not only are important in renal development, but also show promise as a new generation of renal medication and deserve to be tested in clinical trials to clarify their full potential.

Cited by 64 publications

References 93 publications

Retinoic Acid Inhibits HIV-1–Induced Podocyte Proliferation through the cAMP Pathway

Retinoic Acid Inhibits HIV-1–Induced Podocyte Proliferation through the cAMP Pathway

Therapeutic Targets in the Treatment of Allograft Fibrosis

Suppression of nephrin expression by TNF-α via interfering with the cAMP-retinoic acid receptor pathway

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