Circulating fibroblast growth factor-2 precipitates HIV nephropathy in mice

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.