RESUMO
Small interfering RNA (siRNA) delivered from reactive oxygen species-degradable tissue engineering scaffolds promotes diabetic wound healing in rats. Porous poly(thioketal-urethane) scaffolds implanted in diabetic wounds locally deliver siRNA that inhibits the expression of prolyl hydroxylase domain protein 2, thereby increasing the expression of progrowth genes and increasing vasculature, proliferating cells, and tissue development in diabetic wounds.
Assuntos
Diabetes Mellitus/tratamento farmacológico , Pró-Colágeno-Prolina Dioxigenase/administração & dosagem , Pró-Colágeno-Prolina Dioxigenase/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Cicatrização/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Prolina Dioxigenases do Fator Induzível por Hipóxia , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Engenharia Tecidual/métodos , Alicerces Teciduais/químicaRESUMO
The reasons for inadequate production of erythropoietin (EPO) in patients with ESRD are poorly understood. A better understanding of EPO regulation, namely oxygen-dependent hydroxylation of the hypoxia-inducible transcription factor (HIF), may enable targeted pharmacological intervention. Here, we tested the ability of fibrotic kidneys and extrarenal tissues to produce EPO. In this phase 1 study, we used an orally active prolyl-hydroxylase inhibitor, FG-2216, to stabilize HIF independent of oxygen availability in 12 hemodialysis (HD) patients, six of whom were anephric, and in six healthy volunteers. FG-2216 increased plasma EPO levels 30.8-fold in HD patients with kidneys, 14.5-fold in anephric HD patients, and 12.7-fold in healthy volunteers. These data demonstrate that pharmacologic manipulation of the HIF system can stimulate endogenous EPO production. Furthermore, the data indicate that deranged oxygen sensing--not a loss of EPO production capacity--causes renal anemia.
