Human Immunodeficiency Virus-1 Tat Induces Hyperproliferation and Dysregulation of Renal Glomerular Epithelial Cells

Conaldi, Pier Giulio; Bottelli, Antonella; Baj, Andreina; Serra, Caterina; Fiore, Lisa B.; Federico, Giovanni; Bussolati, Benedetta; Camussi, Giovanni

doi:10.1016/s0002-9440(10)64156-9

Cited by 74 publications

(52 citation statements)

References 49 publications

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“…39). Consistently, a lack of statistically significant association between the expression of Mib-1 and HIV-1 positivity was supported by the more rapid cell cycle transition of HeLa cells transfected with HIV-1 Tat protein, as demonstrated by cell counts and in accordance with a previous report by Conaldi et al 40 We expected activation of E2F responsive promoter, due to the important role played by E2Fs during cell cycle progression (reviewed in ref. 41), but when we tested the activity of E2F promoter (Fig.…”

Section: Hiv-1 Tat Oncogenic Role In Cervical Carcinogenesissupporting

confidence: 89%

The effects of HIV-1 Tat protein on cell cycle during cervical carcinogenesis

Nyagol¹,

Leucci²,

Onnis³

et al. 2006

Cancer Biology & Therapy

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The role of HPV in the carcinogenesis of intraepithelial and invasive anogenital lesions is currently well established. E6 and E7 oncoproteins of high-risk HPV genotypes are known to inactivate p53 and pRb pathways. Several studies have described an increased prevalence and recurrence of both cervical HPV infection and invasive cervical cancer among HIV-1 positive women compared to HIV-1 negative cases. For these reasons, cervical cancer is considered an AIDS-defining neoplasm. Unlike other AIDS-associated neoplasms, the occurrence of cervical cancer is independent of immune suppression. HIV-1 infection in patients with high grade precancerous lesions and invasive cervical cancers results in a therapy refractory and more aggressive disease phenotype, which is not yet well understood at the molecular level. An upregulation of HPV E6 and E7 gene expressions by HIV-1 proteins such as Tat has been documented by some authors. However, the role of HIV-1 in cervical carcinomas is still unclear. It is already known that HIV-1 Tat protein is able to influence cell cycle progression. Altogether, these facts led us to investigate the effects of Tat on the expression of cell cycle regulator genes. After transfection of HeLa cells with Tat, we analyzed the expression of cell cycle regulators from these cells by IHC and Real-time PCR. A significant reduction in the expression of cell cycle inhibitors of transcription and an increase in the levels of proliferation markers were observed. These results suggest that HIV-1 may enhance cervical carcinogenesis by promoting cell cycle progression. We also found that this HIV-1 Tat-induced cell proliferation was not dependent on the E2F family of transcription factors, and therefore postulate that Sp factors may be involved.

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Section: Hiv-1 Tat Oncogenic Role In Cervical Carcinogenesissupporting

confidence: 89%

The effects of HIV-1 Tat protein on cell cycle during cervical carcinogenesis

Nyagol¹,

Leucci²,

Onnis³

et al. 2006

Cancer Biology & Therapy

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“…[48][49][50][51][52] After this point, podocytes are considered incapable of undergoing mitosis under normal conditions, although podocyte proliferation occurs in certain pathologic conditions, such as HIVassociated nephropathy. 53,54 Podocytes can be induced to proliferate in vitro when cultured from freshly isolated glomeruli, 55 but these cells express low levels of many of the podocyte-specific differentiation markers, suggesting that podocytes are only capable of proliferating after they have dedifferentiated to a certain degree. Recent evidence suggests that progenitor cells residing in the JGA 56 and Bowman's capsule (PECs) [57][58][59][60][61] may give rise to podocytes.…”

Section: Discussionmentioning

confidence: 99%

Podocyte Number in Children and Adults

Puelles

Douglas-Denton

Cullen‐McEwen

et al. 2015

Journal of the American Society of Nephrology

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Increases in glomerular size occur with normal body growth and in many pathologic conditions. In this study, we determined associations between glomerular size and numbers of glomerular resident cells, with a particular focus on podocytes. Kidneys from 16 male Caucasian-Americans without overt renal disease, including 4 children (#3 years old) to define baseline values of early life and 12 adults ($18 years old), were collected at autopsy in Jackson, Mississippi. We used a combination of immunohistochemistry, confocal microscopy, and design-based stereology to estimate individual glomerular volume (IGV) and numbers of podocytes, nonepithelial cells (NECs; tuft cells other than podocytes), and parietal epithelial cells (PECs). Podocyte density was calculated. Data are reported as medians and interquartile ranges (IQRs). Glomeruli from children were small and contained 452 podocytes (IQR=335-502), 389 NECs (IQR=265-498), and 146 PECs (IQR=111-206). Adult glomeruli contained significantly more cells than glomeruli from children, including 558 podocytes (IQR=431-746; P,0.01), 1383 NECs (IQR=998-2042; P,0.001), and 367 PECs (IQR=309-673; P,0.001). However, large adult glomeruli showed markedly lower podocyte density (183 podocytes per 10 6 mm 3 ) than small glomeruli from adults and children (932 podocytes per 10 6 mm 3 ; P,0.001). In conclusion, large adult glomeruli contained more podocytes than small glomeruli from children and adults, raising questions about the origin of these podocytes. The increased number of podocytes in large glomeruli does not match the increase in glomerular size observed in adults, resulting in relative podocyte depletion. This may render hypertrophic glomeruli susceptible to pathology.

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“…11,12 LRs were also reported to play a critical role modulating Tat activity in other cell types 26,45 ; however, these studies did not explore the specific localization of Tat in LRs. Moreover, to date, the interactions between Tat and LRs in podocytes are unclear, and the residues responsible for the association of Tat with LRs remain undefined.…”

Section: Discussionmentioning

confidence: 99%

“…[6][7][8] A concentration of Tat within the range detected in sera of HIV-infected patients 9,10 can cause glomerular permeability changes in vivo 11 and induce the proliferation of cultured podocytes by stimulating the release of fibroblast growth factor-2 (FGF-2). 12 Indeed, high plasma, kidney, and urinary levels of FGF-2 are detected in children with HIVAN, 13,14 and FGF-2 is accumulated in the kidney of HIV-Tg 26 mice with renal disease. [15][16][17] Overall, these studies suggest that both Tat and FGF-2 may play a role in the pathogenesis of childhood HIVAN.…”

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confidence: 99%

The Basic Domain of HIV-Tat Transactivating Protein Is Essential for Its Targeting to Lipid Rafts and Regulating Fibroblast Growth Factor-2 Signaling in Podocytes Isolated from Children with HIV-1–Associated Nephropathy

Xie¹,

Colberg-Poley

Das³

et al. 2014

Journal of the American Society of Nephrology

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Podocyte injury has a critical role in the pathogenesis of HIV-associated nephropathy (HIVAN). The HIV-1 transactivator of transcription (Tat), combined with fibroblast growth factor-2 (FGF-2), can induce the dedifferentiation and proliferation of cultured human podocytes. Cellular internalization of Tat requires interactions with heparan sulfate proteoglycans and cholesterol-enriched lipid rafts (LRs). However, the specific distribution of Tat in human podocytes and its ability to associate with LRs have not been documented. Here, we found that Tat is preferentially recruited to LRs in podocytes isolated from children with HIVAN. Furthermore, we identified arginines in the basic domain (RKKRRQRRR) of Tat as essential for (1) targeting Tat to LRs, (2) Tat-mediated increases in the expression of Rho-A and matrix metalloproteinase-9 in LRs, and (3) Tat-mediated enhancement of FGF-2 signaling in human podocytes and HIV-transgenic mouse kidneys and the exacerbation of renal lesions in these mice. Tat carrying alanine substitutions in the basic domain (AKKAAQAAA) remained localized in the cytosol and did not associate with LRs or enhance FGF-2 signaling in cultured podocytes. These results show the specific association of Tat with LRs in podocytes isolated from children with HIVAN, confirm Tat as a regulator of FGF-2 signaling in LRs, and identify the key domain of Tat responsible for promoting these effects and aggravating renal injury in HIV-transgenic mice. Moreover, these results provide a molecular framework for developing novel therapies to improve the clinical outcome of children with HIVAN.

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Human Immunodeficiency Virus-1 Tat Induces Hyperproliferation and Dysregulation of Renal Glomerular Epithelial Cells

Cited by 74 publications

References 49 publications

The effects of HIV-1 Tat protein on cell cycle during cervical carcinogenesis

The effects of HIV-1 Tat protein on cell cycle during cervical carcinogenesis

Podocyte Number in Children and Adults

The Basic Domain of HIV-Tat Transactivating Protein Is Essential for Its Targeting to Lipid Rafts and Regulating Fibroblast Growth Factor-2 Signaling in Podocytes Isolated from Children with HIV-1–Associated Nephropathy

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