Severe anemia and iron deficiency are common complications in chronic kidney disease. The cause of renal anemia is multifactorial and includes decreased erythropoietin (Epo) production, iron deficiency, and inflammation, and it is currently treated with injections of synthetic Epo. However, the use of recombinant Epo has several adverse effects. We previously reported that high fibroblast growth factor 23 (FGF23) levels in mice are associated with decreased red blood cell production, whereas genetic inactivation of Fgf23 results in expansion of the erythroid lineage. The present study is the first to show that high FGF23 levels in a mouse model of renal failure contribute to renal anemia, and inhibiting FGF23 signaling stimulates erythropoiesis and abolishes anemia and iron deficiency. Moreover, we show that inhibition of FGF23 signaling significantly decreases erythroid cell apoptosis and influences the commitment of hematopoietic stem cells toward the erythroid linage. Furthermore, we show that blocking FGF23 signaling attenuates inflammation, resulting in increased serum iron and ferritin levels. Our data clearly demonstrate that elevated FGF23 is a causative factor in the development of renal anemia and iron deficiency, and importantly, blocking FGF23 signaling represents a novel approach to stimulate erythropoiesis and possibly improve survival for millions of chronic kidney disease patients worldwide.-Agoro, R., Montagna, A., Goetz, R., Aligbe, O., Singh, G., Coe, L. M., Mohammadi, M., Rivella, S., Sitara, D. Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia.

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The role of nitric oxide (NO) in the cardiovascular actions of diaspirin cross-linked hemoglobin (DCLHb) was studied in anesthetized rats. The regional circulatory and systemic hemodynamic effects of DCLHb (400 mg/kg iv) were studied using a radioactive microsphere technique in control (untreated) and L-arginine (a NO precursor) pretreated rats. DCLHb produced a significant increase in blood pressure (75%), cardiac output (42%), stroke volume (36%), and total peripheral resistance (45%), without affecting heart rate, when administered to control rats. L-Arginine pretreatment significantly attenuated DCLHb-induced systemic hemodynamic effects. DCLHb-induced increase in blood flow to the skin and spleen was completely blocked, and that to the heart was partially blocked, by L-arginine pretreatment, suggesting that cardiovascular actions induced by DCLHb could be antagonized by the NO precursor L-arginine. The NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) produced significant increases in regional vascular resistance, leading to a decrease in blood flow to all the organs except the heart, where an increase in blood flow and a decrease in vascular resistance was observed. DCLHb, when administered in L-NAME-pretreated rats, accentuated the decrease in blood flow to the gastrointestinal system, spleen, mesentery and pancreas, skin, and musculoskeletal system. These studies provide evidence that the NO precursor L-arginine can attenuate the effects of DCLHb and that DCLHb can potentiate the effect of the NOS inhibitor L-NAME. The role of NO in the mechanism of action of DCLHb was further studied by estimating plasma guanosine 3',5'-cyclic monophosphate (cGMP) in control, DCLHb-treated, L-NAME-treated, and L-NAME followed by DCLHb-treated rats. DCLHb and L-NAME significantly decreased the concentration of circulating cGMP in blood plasma. L-NAME pretreatment potentiated DCLHb-induced decrease in cGMP levels. Because the formation of cGMP is stimulated by NO, these studies provide additional evidence for the involvement of NO in the mechanism of action of DCLHb. It is concluded that NO plays an important role in the cardiovascular effects of DCLHb.

The adult human anterior cruciate ligament (ACL) has poor functional healing response. Transforming growth factor (TGF)-β1 enhances the wound repair by stimulating matrix proteins deposition as well as the proliferation and migration of cells. However, the function of the TGF-β1-induced matrix metalloproteinases' (MMPs) activities in the wound healing process is poorly understood. In this study, exogenous MMP-2 is added to mimic the TGF-β1-induced MMP-2 expression. Role of NF-κB pathway is further examined. Our results show that TGF-β1 induces dramatic elevation of MMP-2 activities and the MMP-2/tissue inhibitors of metalloproteinases ratio. Furthermore, the exogenous MMP-2 significantly promoted in vitro wound healing abilities of ACL fibroblasts that are significantly blocked with the addition of its inhibitors. TGF-β1 also increases the proliferation of ACL fibroblasts whereas MMP-2 alone does not, indicating that MMP-2 activities are not involved in the proliferation. TGF-β1-induced MMP-2 activity is inhibited by Bay11-7082 and Bay11-7085 (NF-κB inhibitors). Our results demonstrate that increased TGF-β1 facilitates the ACL healing process by promoting the fibroblasts migration and proliferation. The migration process is mediated by MMP-2 and NF-κB pathway is involved in TGF-β1-mediated MMP-2 release.