Role of circulating fibroblast growth factor-2 in lipopolysaccharide-induced acute kidney injury in mice

Abstract

Background Fibroblast Growth Factor (FGF-2) is an angiogenic growth factor involved in renal growth and regeneration. Previous studies in rodents showed that single intrarenal injections of FGF-2 improved the outcome of acute kidney injury (AKI). Septic children usually show elevated plasma levels of FGF-2, and are at risk of developing AKI. However, the role of circulating FGF-2 in the pathogenesis of AKI is not well understood. Methods Here, we developed a mouse model to determine how FGF-2 released into the circulation modulates the outcome of AKI induced by lipopolysaccharide (LPS). Young FVB/N mice were infected with adenoviruses carrying a secreted form of human FGF-2 or control LacZ vectors. Subsequently, when the circulating levels of FGF-2 were similar to those seen in septic children, mice were injected with a non-lethal dose of LPS or control buffer. Results All mice injected with LPS developed hypotension and AKI, and recovered after five days. FGF-2 did not improve the outcome of AKI, and induced more significant renal proliferative and apoptotic changes during the recovery phase. Conclusions These findings suggest that circulating FGF-2 may not necessarily prevent the development or improve the outcome of AKI. Moreover, the renal accumulation of FGF-2 might cause further renal damage.

A pilot study of urinary fibroblast growth factor-2 and epithelial growth factor as potential biomarkers of acute kidney injury in critically ill children

“…This is consistent with our previous findings showing elevated urinary levels of FGF-2 in children with classic and atypical forms of HUS [44, 56]. Other studies done in different rodent models of acute kidney injury induced by renal ischemia [34, 35] or lipopolysaccharide injections [36, 37] also support the notion that FGF-2 plays a critical role in the outcome of AKI. In our study, FGF-2 was not as sensitive as urinary NGAL to detect AKI in critically ill children; however, the use of both biomarkers combined improved the specificity of this test to identify AKI, relative to the use of each biomarker alone.…”

“…Moreover, the release of angiogenic factors in the plasma of critically ill children can be associated with a worse clinical outcome [31]. Furthermore, studies done in experimental animal models of AKI induced by renal ischemia [34, 35] or lipopolysaccharide injections [36, 37], have shown that the administration of angiogenic factors, such as fibroblast growth factor −2 (FGF-2), can affect the outcome of AKI. In addition, previous studies have shown that the urinary levels of epidermal growth factor (EGF) can been used to predict and/or monitor the outcome of AKI, both in children [38–40] and adults [41].…”

The Basic Domain of HIV-Tat Transactivating Protein Is Essential for Its Targeting to Lipid Rafts and Regulating Fibroblast Growth Factor-2 Signaling in Podocytes Isolated from Children with HIV-1–Associated Nephropathy

“…In this experimental adult mouse model, 38,39 only the hepatocytes are infected with the adenoviral vectors, and FGF-2 released into the circulation is trapped in the kidney bound to HSPGs. 13,15,16,36,40 As shown in Figure 8, FGF-2 increased the renal expression of pERK, Rho-A, pMLC 2 , and MMP-9 in both WT and HIV-Tg 26 mice.…”

“…In other experiments, WT or HIV-Tg 26 adult male mice without preexisting renal disease were divided in two groups (n=3-5 mice per group) and injected through the retro-orbital vein plexus with adenoviral vectors carrying LacZ or a 700-bp cDNA sequence encoding a secreted form of human FGF-2 (rAd-FGF-2; 5310 8 pfu/mouse) as previously described. 38,69,70 Mice were euthanized 7 or 28 days after the adenoviral infection, and their kidneys were processed for signaling or renal histologic studies as described above. Renal injury was assessed in sections stained with period acid-Schiff by counting the percentage of glomeruli exhibiting segmental/global sclerosis and the percentage of tubular casts and microcysts.…”

“…In addition, we counted the number of cells that stained positive for proliferating cell nuclear antigen and WT-1 and assessed the magnitude of albuminuria as previously described. 38 …”