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Circulating fibroblast growth factor-2 precipitates HIV nephropathy in mice
Jharna R Das1,2, Marina Jerebtsova1,2, Pingtao Tang1,2
1Children's National Hospital, Washington, DC 20010, USA.
Insights
High levels of fibroblast growth factor-2 (FGF-2) may precipitate kidney disease in children with human immunodeficiency virus-1 (HIV-1). This study in mice suggests FGF-2 is a risk factor for HIV-associated nephropathy (HIVAN).
Area of Science:
- Nephrology
- Virology
- Molecular Biology
Background:
- People of African ancestry with human immunodeficiency virus-1 (HIV-1) are susceptible to HIV-associated nephropathy (HIVAN).
- Elevated plasma fibroblast growth factor-2 (FGF-2) is common in children with HIVAN, but its role in disease development is unknown.
- Understanding FGF-2's role is crucial for managing childhood HIVAN.
Purpose of the Study:
- To investigate the impact of circulating FGF-2 on the progression of HIVAN in young HIV-Tg26 mice.
- To determine if FGF-2 contributes to the pathogenesis of HIVAN independently of HIV-1 gene expression.
Main Methods:
- Utilized HIV-Tg26 mice and wild-type mice.
- Administered recombinant adenoviral FGF-2 (rAd-FGF-2) vectors to induce FGF-2 expression.
- Assessed kidney lesions, proteinuria, glomerular size, and inflammatory markers.
- Investigated the role of phosphorylated extracellular signal-regulated kinase (pERK) pathway.
- Evaluated the therapeutic effect of the tyrosine kinase inhibitor PD173074.
Main Results:
- FGF-2 was recruited to kidneys, activating pERK in renal epithelial cells and causing HIVAN-like lesions, including proteinuria and glomerular enlargement, in wild-type mice.
- HIV-Tg26 mice treated with rAd-FGF-2 exhibited exacerbated proliferative, pro-fibrotic, and inflammatory kidney lesions, mimicking human childhood HIVAN.
- Treatment with PD173074 partially reversed these FGF-2-induced lesions.
Conclusions:
- Circulating FGF-2 can precipitate HIVAN-like kidney disease by activating pERK in renal epithelial cells, independent of HIV-1 gene expression.
- High plasma FGF-2 levels represent a potential independent risk factor for the development of HIVAN in young children.
- Targeting FGF/VEGF receptor tyrosine kinases may offer a therapeutic strategy for managing HIVAN.
Abstract:
People of African ancestry living with the human immunodeficiency virus-1 (HIV-1) are at risk of developing HIV-associated nephropathy (HIVAN). Children with HIVAN frequently show high plasma fibroblast growth factor-2 (FGF-2) levels; however, the role of circulating FGF-2 in the pathogenesis of childhood HIVAN is unclear. Here, we explored how circulating FGF-2 affected the outcome of HIVAN in young HIV-Tg26 mice. Briefly, we demonstrated that FGF-2 was preferentially recruited in the kidneys of mice without pre-existing kidney disease, precipitating HIVAN by activating phosphorylated extracellular signal-regulated kinase (pERK) in renal epithelial cells, without inducing the expression of HIV-1 genes. Wild-type mice injected with recombinant adenoviral FGF-2 (rAd-FGF-2) vectors 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 vectors developed more-significant proliferative and pro-fibrotic inflammatory lesions, similar to those seen in childhood HIVAN. These lesions were partially reversed by treating mice with the FGF/VEGF receptor tyrosine kinase inhibitor PD173074. These findings suggest that high plasma FGF-2 levels may be an independent risk factor for precipitating HIVAN in young children.
