An HIV-Tat inducible mouse model system of childhood HIV-associated nephropathy

Tang, Pingtao; Das, Jharna R.; Li, Jinliang; Yu, Jing; Ray, Patricio E.

doi:10.1242/dmm.045641

Cited by 6 publications

(2 citation statements)

References 62 publications

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“…These findings are in agreement with the notion that other viral proteins and heparin-binding growth factors that are involved in the pathogenesis of HIVAN (e.g. Nef, Tat, VEGF-A) ( He et al, 2004 ; Das et al, 2016 ; Korgaonkar et al, 2008 ; Tang et al, 2020 ) also activate the pERK pathway and can act in synergy with FGF-2 ( Seghezzi et al, 1998 ). Nonetheless, PD170374 did not completely normalize the proteinuria or completely reverse the renal histological lesions in HIV-Tg 26 mice injected with rAd-FGF-2 vectors.…”

Section: Discussionsupporting

confidence: 91%

Circulating Fibroblast Growth Factor-2 precipitates HIV-nephropathy in mice

Das

Jerebtsova

Tang

et al. 2021

Disease Models &Amp; Mechanisms

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Over 80% of all children living with HIV reside in Africa and are at risk of developing HIV-associated nephropathy (HIVAN). Once HIVAN is established in children, it is difficult to revert its progression to chronic kidney failure even using antiretroviral drugs. Therefore, new therapeutic strategies are needed. Previous studies showed that the risk of developing HIVAN increases in children with high circulating levels of FGF-2, but it is unclear whether FGF-2 per se precipitates HIVAN. To unravel the role of circulating FGF-2 in childhood HIVAN, we used the HIV-Tg26 mouse model of HIVAN. Briefly, we demonstrated that circulating FGF-2 was preferentially recruited in the kidney of HIV-Tg26 mice with renal disease, and precipitated HIVAN in young mice without pre-existing kidney disease by activating the pERK pathway in renal epithelial cells without previously inducing the expression of HIV-1 genes. Wild type mice injected with recombinant adenoviral FGF-2 vectors (rAd-FGF-2) carrying a secreted form of human FGF-2 developed transient and reversible HIVAN-like lesions, including proteinuria and glomerular enlargement. HIV-Tg26 mice injected with rAd-FGF-2 developed more significant proliferative and pro-fibrotic inflammatory lesions, similar to those seen in childhood HIVAN. These lesions were partially reversed in mice treated with the FGF/VEGF receptor tyrosine kinase inhibitor PD173074. In conclusion, we developed a new FGF-2-inducible model of childhood HIVAN, and showed that high circulating levels of FGF-2 precipitated HIVAN without inducing the renal expression of HIV-genes. These findings suggest that high plasma FGF-2 levels may be an independent risk factor for precipitating HIVAN in young children.

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Section: Discussionsupporting

confidence: 91%

Circulating Fibroblast Growth Factor-2 precipitates HIV-nephropathy in mice

Das

Jerebtsova

Tang

et al. 2021

Disease Models &Amp; Mechanisms

Self Cite

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“…In support of these findings, the HIV-Tat protein can interact with the extracellular domain of the Notch receptors and was suggested as a non-canonical ligand for Notch activation [50][51][52][53] . In addition, previous studies in HIV-Tg26 mice and human podocytes showed that HIV-1 can precipitate the development of HIVAN and affect the cytoskeletal structure of podocytes cultured from children with HIVAN 54,55 . Moreover, there are two RBP-JK binding sites adjacent to the NFκB binding sites on the HIV-LTR promoter.…”

Section: Discussionmentioning

confidence: 96%

Notch3 deletion regulates HIV-1 gene expression and systemic inflammation to ameliorate chronic kidney disease

Thornton,

Sommer,

McGonigle

et al. 2023

Preprint

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Antiretroviral therapy (ART) has profoundly decreased HIV-1 associated morbidity. However, despite ART, immune cells remain latently infected and slowly release viral proteins, leading to chronic inflammation and HIV associated comorbidities. Thus, new strategies are needed to reduce the inflammatory effects of HIV-1. In previous studies we found that gamma secretase inhibitor (GSIXX) ameliorated renal lesions of HIV-Tg26 mice carrying replication defective HIV-1 PNL4-3 by inhibiting Notch activation. Since gamma secretase inhibition is not a safe strategy in humans, here we examined the specific role of the Notch3 pathway in the pathogenesis of the renal lesions and outcome of HIV-Tg26 mice. We found that Notch3 is activated in podocytes and other renal cells in HIV-Tg26 mice and human biopsies with HIV-1 associated Nephropathy (HIVAN). Knockdown of Notch3 in HIV-Tg26 mice revealed a marked reduction in the mortality rate, improvement in renal injury and function. RNA sequencing and immunolabeling data revealed that Notch3 deletion drastically reduced infiltrating renal macrophages in HIV-Tg-N3KO mice in association with renal reduction of HIV-nefmRNA expression levels. In fact, bone marrow derived macrophages from HIV-Tg26 mice showed a significant activation of Notch3 signaling. Further, systemic levels of TNF-alpha and MCP-1 and other inflammatory chemokines and cytokines were reduced in Tg-N3KO mice as compared to HIV-Tg26 mice and this translated to a marked reduction of HIV-induced skin lesions. Taken together, these studies strongly point to a dual inhibitory/therapeutic effect of Notch3 inhibition on HIV-induced systemic, skin and renal lesions independently of ART.Translational statementNotch3 inhibition has been reported to be an anti-inflammatory strategy for glomerular diseases. Here, using an HIV-1 transgenic mouse model we show that global Notch3 deletion not only improves kidney phenotype but also renal expression of HIV gene, Nef and systemic inflammation which leads to a drastic increase of life span of these mice. Notch3 inhibition can thus play a dual protective role in HIV related chronic diseases.

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