Critical role for Nef in HIV-1–induced podocyte dedifferentiation

Sunamoto, Masaaki; Husain, Mohammad; He, John Cijiang; Schwartz, Ernest; Klotman, Paul E.

doi:10.1046/j.1523-1755.2003.00283.x

Cited by 68 publications

(59 citation statements)

References 21 publications

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“…27 Production of HIV-1 constructs has been described previously. 9 The podocytes used in these experiments are from an established line of pNL4-3:d1443 and pHR-CMV-IRES2-GFP-⌬B-infected podocytes. In all experiments, cells were grown at 37°C on type 1 collagen-coated dishes for 10 d to inactivate temperature-sensitive T antigen and allow for differentiation.…”

Section: Conditionally Immortalized Murine Podocytes With Hiv-1-exprementioning

confidence: 99%

“…9,15,16 In vitro studies support a clear role for Nef in podocyte proliferation and de-differentiation 9 ; therefore, we determined whether VEGF mediates HIV/Nef-induced podocyte proliferation. We found that treatment with exogenous VEGF significantly increased podocyte number ( Figure 3A).…”

mentioning

confidence: 99%

“…7 The collapsing glomerular lesions that are classically seen in HIVAN are associated with podocyte proliferation and loss of podocyte differentiation markers, including WT1 and synaptopodin. 8,9 In this study, we sought to determine whether VEGF is upregulated in podocytes from mice with HIVAN and whether blockade of VEGF receptors can ameliorate the podocyte proliferation and de-differentiation induced by HIV.…”

mentioning

confidence: 99%

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HIV-1 Upregulates VEGF in Podocytes

Korgaonkar

Feng²,

Ross³

et al. 2008

Journal of the American Society of Nephrology

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Section: Conditionally Immortalized Murine Podocytes With Hiv-1-exprementioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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HIV-1 Upregulates VEGF in Podocytes

Korgaonkar

Feng²,

Ross³

et al. 2008

Journal of the American Society of Nephrology

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“…In vitro, infection of podocytes with HIV-1 also causes proliferation and dedifferentiation (8). We have shown that the HIV-1 nef gene is the major determinant of podocyte proliferation and dedifferentiation (8,9) by inducing Src-dependent mitogen-activated protein kinase (MAPK) 1 and 2/Stat3 activation (10).…”

mentioning

confidence: 99%

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

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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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“…Unlike most other glomerulopathies, HIVAN is characterized by proliferation and dedifferentiation of podocytes, which are glomerular visceral epithelial cells (3,4,17). Recently, we showed that the HIV-1 nef gene is the primary determinant of this unusual podocyte phenotype (17,36) and that Nef stimulates podocyte proliferation and dedifferentiation through the Src-dependent mitogenactivated protein kinase 1,2 (MAPK1,2) pathways (15). Increased MAPK1,2 phosphorylation is also observed in mouse and human kidney sections of HIVAN (15).…”

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confidence: 99%

Retinoic Acid Utilizes CREB and USF1 in a Transcriptional Feed-Forward Loop in Order To Stimulate MKP1 Expression in Human Immunodeficiency Virus-Infected Podocytes

Lu¹,

Wang

Feng

et al. 2008

Molecular and Cellular Biology

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Nef-induced podocyte proliferation and dedifferentiation via mitogen-activated protein kinase 1,2 (MAPK1,2) activation plays a role in human immunodeficiency virus (HIV) nephropathy pathogenesis. Alltrans retinoic acid (atRA) reverses the HIV-induced podocyte phenotype by activating cyclic AMP (cAMP)/ protein kinase A (PKA) and inhibiting MAPK1,2. Here we show that atRA, through cAMP and PKA, triggers a feed-forward loop involving CREB and USF1 to induce biphasic stimulation of MKP1. atRA stimulated CREB and USF1 binding to the MKP1 gene promoter, as shown by gel shifting and chromatin immunoprecipitation assays. CREB directly mediated the early phase of atRA-induced MKP1 stimulation; whereas the later phase was mediated by CREB indirectly through induction of USF1. These findings were confirmed by a reporter gene assay using the MKP1 promoter with mutation of CRE or Ebox binding sites. Consistent with these findings, the biological effects of atRA on podocytes were inhibited by silencing either MKP1, CREB, or USF1 with small interfering RNA. atRA also induced CREB phosphorylation and MKP1 expression and reduced MAPK1,2 phosphorylation in kidneys of HIV type 1-infected transgenic mice. We conclude that atRA induces sustained activation of MKP1 to suppress Nef-induced activation of the Src-MAPK1,2 pathway, thus returning the podocyte to a more differentiated state. The mechanism involves a feed-forward loop where activation of one transcription factor (TF) (CREB) leads to induction of a second TF (USF1).

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Critical role for Nef in HIV-1–induced podocyte dedifferentiation

Cited by 68 publications

References 21 publications

HIV-1 Upregulates VEGF in Podocytes

HIV-1 Upregulates VEGF in Podocytes

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

Retinoic Acid Utilizes CREB and USF1 in a Transcriptional Feed-Forward Loop in Order To Stimulate MKP1 Expression in Human Immunodeficiency Virus-Infected Podocytes

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