Circulating fibroblast growth factor-2 precipitates HIV nephropathy in mice

• Published in: Disease models & mechanisms Vol. 14; no. 7
• Main Authors: Das, Jharna R, Jerebtsova, Marina, Tang, Pingtao, Li, Jinliang, Yu, Jing, Ray, Patricio E
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01-07-2021; The Company of Biologists
• Subjects: AIDS-Associated Nephropathy - genetics; Animals; Binding sites; Blood vessels; Child, Preschool; children; Disease Models, Animal; Fibroblast Growth Factor 2; Fibroblasts; Growth factors; HIV; hiv kidney diseases; hiv nephropathy; HIV-1 - genetics; Human immunodeficiency virus; Humans; Kidney diseases; Mice; Mice, Transgenic; Microscopy; Plasma; HIV nephropathy; Children; Fibroblast growth factor-2; HIV kidney diseases
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.048980

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.