A novel role of fibroblast growth factor-2 and pentosan polysulfate in the pathogenesis of intestinal bleeding in mice

Jerebtsova, Marina; Wong, Edward C.C.; Przygodzki, Ronald; Tang, Pingtao; Ray, Patricio E.

doi:10.1152/ajpheart.00969.2006

Cited by 20 publications

(23 citation statements)

References 34 publications

(41 reference statements)

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“…The particle-to-plaque-forming unit (pfu) ratio of the virus stock used in these experiments was 100. Mice were injected via the retro-orbital vein plexus with 5 × 10 8 pfu/mouse of either rAd vector, as described before [22]. Blood samples were taken in four mice 72 hours after the injection of adenoviral vectors, to assess the plasma levels of FGF- 2 by ELISA (R&D kit.…”

Section: Methodsmentioning

confidence: 99%

“…Blood samples were taken in four mice 72 hours after the injection of adenoviral vectors, to assess the plasma levels of FGF- 2 by ELISA (R&D kit. Minneapolis, MN), as previously described [22]. …”

Section: Methodsmentioning

confidence: 99%

“…Paraffin embedded sections were cut at 5 m, deparaffinized, rehydrated, and stained with hematoxylin and eosin or Masson’s trichrome as previously described [22]. For immunohistochemistry studies, the renal sections were heated twice for five minutes each in 0.01mol/L sodium citrate (pH 6.0) in a microwave oven (2450 mHz, 850 W) to augment antigen retrieval.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2011

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

et al. 2011

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“…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.…”

Section: Arginines In the Tat Basic Domain Sequences Mediate Lr Assocmentioning

confidence: 99%

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

Xie¹,

Colberg-Poley

Das³

et al. 2014

Journal of the American Society of Nephrology

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Podocyte injury has a critical role in the pathogenesis of HIV-associated nephropathy (HIVAN). The HIV-1 transactivator of transcription (Tat), combined with fibroblast growth factor-2 (FGF-2), can induce the dedifferentiation and proliferation of cultured human podocytes. Cellular internalization of Tat requires interactions with heparan sulfate proteoglycans and cholesterol-enriched lipid rafts (LRs). However, the specific distribution of Tat in human podocytes and its ability to associate with LRs have not been documented. Here, we found that Tat is preferentially recruited to LRs in podocytes isolated from children with HIVAN. Furthermore, we identified arginines in the basic domain (RKKRRQRRR) of Tat as essential for (1) targeting Tat to LRs, (2) Tat-mediated increases in the expression of Rho-A and matrix metalloproteinase-9 in LRs, and (3) Tat-mediated enhancement of FGF-2 signaling in human podocytes and HIV-transgenic mouse kidneys and the exacerbation of renal lesions in these mice. Tat carrying alanine substitutions in the basic domain (AKKAAQAAA) remained localized in the cytosol and did not associate with LRs or enhance FGF-2 signaling in cultured podocytes. These results show the specific association of Tat with LRs in podocytes isolated from children with HIVAN, confirm Tat as a regulator of FGF-2 signaling in LRs, and identify the key domain of Tat responsible for promoting these effects and aggravating renal injury in HIV-transgenic mice. Moreover, these results provide a molecular framework for developing novel therapies to improve the clinical outcome of children with HIVAN.

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“…Also, a few cases of thrombocytopenia and venous thrombosis have been reported in patients taking pentosan polysulfate (Tardy-Poncet et al 1994). These incidences of bleeding were mainly attributed to Elmiron ® ’s structural and functional similarity to the anticoagulant, heparin (Jerebtsova et al 2007; Marshall et al 1997). Interestingly, a few cases of treatment-induced thrombocytopenia were suggested to be due to immune-mediated responses however the exact immune mechanisms are unknown (Bollaert et al 1986; Gironell et al 1996).…”

Section: Introductionmentioning

confidence: 99%

Immunomodulatory activity of orphan drug Elmiron® in female B6C3F1/N mice

Thakur

Nyska

White

et al. 2014

Food and Chemical Toxicology

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Interstitial cystitis (IC) is a chronic disorder characterized by bladder discomfort and urinary urgency in the absence of identifiable infection. Despite the expanding use in treatment of IC and other chronic conditions, the effects of Elmiron® treatment on immune system remain unknown. Therefore, female B6C3F1/N mice were orally administered Elmiron® daily for 28-days at doses of 63, 125, 250, 500 or 1000 mg/kg to evaluate its immunomodulatory effects. Mice treated with Elmiron® had a significant increase in absolute numbers of splenic macrophages (63, 500 and 1000 mg/kg) and natural killer (NK) cells (250 and 1000 mg/kg). Elmiron® treatment did not affect the humoral immune response or T cell proliferative response. However, innate immune responses such as phagocytosis by liver macrophages (1000 mg/kg) and NK cell activity were enhanced (500 and 1000 mg/kg). Further analysis using a disease resistance model showed that Elmiron® -treated mice demonstrated significantly increased anti-tumor activity against B16F10 melanoma cells at the 500 and 1000 mg/kg doses. Collectively, we conclude that Elmiron® administration stimulates the immune system, increasing numbers of specific cell populations and enhancing macrophage phagocytosis and NK cell activity in female B6C3F1/N mice. This augmentation may have largely contributed to the reduced number of B16F10 melanoma tumors.

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A novel role of fibroblast growth factor-2 and pentosan polysulfate in the pathogenesis of intestinal bleeding in mice

Abstract: Jerebtsova M, Wong E, Przygodzki R, Tang P, Ray PE. A novel role of fibroblast growth factor-2 and pentosan polysulfate in the pathogenesis of intestinal bleeding in mice.

Cited by 20 publications

References 34 publications

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

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

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

Immunomodulatory activity of orphan drug Elmiron® in female B6C3F1/N mice

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