RGD Reference Report - Retinoic acid inhibits HIV-1-induced podocyte proliferation through the cAMP pathway. - Rat Genome Database

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Retinoic acid inhibits HIV-1-induced podocyte proliferation through the cAMP pathway.

Authors: He, John Cijiang  Lu, Ting-Chi  Fleet, Margaret  Sunamoto, Masaaki  Husain, Mohammad  Fang, Wei  Neves, Susana  Chen, Yibang  Shankland, Stuart  Iyengar, Ravi  Klotman, Paul E 
Citation: He JC, etal., J Am Soc Nephrol. 2007 Jan;18(1):93-102. doi: 10.1681/ASN.2006070727. Epub 2006 Dec 20.
RGD ID: 38599009
Pubmed: PMID:17182884   (View Abstract at PubMed)
PMCID: PMC3197239   (View Article at PubMed Central)
DOI: DOI:10.1681/ASN.2006070727   (Journal Full-text)

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 RXRgamma. RARalpha antagonists blocked atRA-induced cAMP production and its antiproliferative and prodifferentiation effects on podocytes, suggesting that RARalpha 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 RARalpha-mediated intracellular cAMP production. These results demonstrate the mechanism by which atRA reverses the proliferation of podocytes that is induced by HIV-1.



Gene-Chemical Interaction Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
NPHS1Humanretinoic acid increases expression ISONphs1 (Mus musculus)Retinoic acid increases expression of Nphs1 mRNA in podocyteRGD 
Nphs1Ratretinoic acid increases expression ISONphs1 (Mus musculus)Retinoic acid increases expression of Nphs1 mRNA in podocyteRGD 
Nphs1Mouseretinoic acid increases expression IEP Retinoic acid increases expression of Nphs1 mRNA in podocyteRGD 

Objects Annotated

Genes (Rattus norvegicus)
Nphs1  (NPHS1 adhesion molecule, nephrin)

Genes (Mus musculus)
Nphs1  (nephrosis 1, nephrin)

Genes (Homo sapiens)
NPHS1  (NPHS1 adhesion molecule, nephrin)


Additional Information