A high proportion of children of African descent living with human immunodeficiency virus-1 (HIV-1) will develop HIV-associated nephropathy (HIVAN), which presents as progressive renal failure and heavy proteinuria. Many children with HIVAN have high levels of fibroblast growth factor-2 (FGF-2) in their plasma and urine. FGF-2 is a heparin-binding growth factor that plays an important role in renal development and regeneration after injury. Increased FGF-2 secretion has been attributed to endothelial cell injury, cytokines and proteases associated with HIV-infected cells.
Patricio Ray and colleagues investigated the role of FGF-2 in HIVAN (Das et al., 2021). HIV-Tg26 mice express HIV genes in the kidneys and other tissues and can spontaneously develop HIVAN at ∼45-90 days. The authors injected young HIV-Tg26 mice that have not yet spontaneously developed HIVAN with recombinant human (rh) FGF-2 for 7 days, and, for a longer-lasting effect, transduced the mice with an adenoviral vector encoding rh-FGF-2. HIV-Tg26 mice had prolonged retention of increased levels of rh-FGF-2 in the kidneys compared to WT mice, owing to higher expression of FGF receptors. However, both WT and HIV-Tg26 mice developed HIVAN features, such as characteristic renal histology, proteinuria, tubular dilatation and renal inflammation, although HIV-Tg26 mice developed a more complete HIVAN phenotype, with increased renal glomeruli size, increased renal epithelial cell proliferation and decreased expression of podocyte differentiation markers. Importantly, this FGF-2-inducible model recapitulated the changes seen in children with HIVAN. Clinical signs of HIVAN were reversed in WT mice when FGF-2 levels decreased, and, in HIV-Tg26 mice, an FGF/VEGF receptor tyrosine kinase inhibitor that blocks the phosphorylated extracellular signal-regulated kinase (pERK) pathway partially prevented the FGF-2-induced phenotype. This signifies that FGF-2 acts, at least in part, via the pERK pathway in kidney cells.
This study demonstrates that circulating FGF-2 can induce an HIVAN-like nephropathy phenotype without pre-existing HIV-1 gene expression by activating the pERK pathway. Children living with HIV can develop HIVAN despite modern antiretroviral treatments. Therefore, understanding childhood HIVAN is imperative to prevent its onset. Circulating FGF-2 could potentially be used as an independent risk factor for childhood HIVAN, and this novel mouse model can be used to test interventions to prevent HIVAN development and progression in children.