Erythropoietin Protects the Kidney by Regulating the Effect of TNF-α in L-NAME-Induced Hypertensive Rats

Abstract

Background/Aims: Hypertension is the leading cause of death worldwide. Chronic high blood pressure induces inflammation. Tumor necrosis factor (TNF)-α plays a major role in inflammation and also depresses the synthesis of erythropoietin, which exerts protective effects on tissue; however, the mechanism is still unclear. We investigated the protective effect of erythropoietin against tissue damage caused by hypertension in the kidney and whether this effect was suppressed by TNF-α. Methods: First, we detected the optimum chronic dose for darbepoetin-α (Depo), which is a long-acting erythropoietin analog for rats. We separated 60 female adult rats into 6 groups: control, N^ω-nitro-L-arginine methyl ester hydrochloride (L-NAME), L-NAME+Depo, L-NAME+Remicade (an anti-TNF-α antibody), L-NAME+Depo+Remicade, Depo, and control. After 1 month of treatment, we measured cardiovascular parameters, took blood samples, sacrificed the rats, and removed kidneys for analyses. Results: The apoptotic index and the plasma and kidney mRNA levels of TNF-α increased in the L-NAME group and decreased in all other treatment groups. Macrophage accumulation increased in the L-NAME and L-NAME+Remicade groups, while it decreased in the Depo group. The mRNA abundance of TNF receptor 1 (TNFR1) decreased slightly in the Depo group and TNFR2 increased significantly in the same group. Conclusion: Erythropoietin protects kidney tissue against hypertension by preventing the apoptotic effects of TNF-α by blocking macrophage accumulation, decreasing TNF-α levels, and switching the TNF-α receptors from the apoptotic receptor TNFR1 to the proliferative receptor TNFR2.

miR663 Prevents Epo Inhibition Caused by TNF-Alpha in Normoxia and Hypoxia

“…In vivo and in vitro studies on astrocytes have shown that TNF- α suppresses hypoxia-induced Epo expression also in a dose-dependent manner [ 11 ]. In our previous study, we have shown that elevated levels of TNF- α in hypertension decreased the amount of Epo in the circulation and that circulating Epo concentrations increased to normal values when TNF- α was blocked with anti-TNF- α antibodies [ 12 ].…”

Efeito da hipóxia na patogênese da lesão renal em dois modelos experimentais de doença renal crônica: agravamento ou proteção?

“…Outra função da EPO é proteger contra injúria renal, reduzindo a apoptose e a inflamação e aumentando a proliferação tubular (179). A EPO renal é expressa principalmente pelos pericitos (células semelhantes a fibroblastos) e em um quadro de DRC, essas células se transdiferenciam em miofibroblastos cuja capacidade de produção de EPO é reduzida (180).Achados corroboram a ideia de que a interação entre EPO e NO representam um mecanismo relevante de atenuar os danos causados pela hipertensão (181)(182)(183) e que a exposição à hipóxia crônica pode ser uma estratégia terapêutica para elevar os níveis de EPO e outros mecanismos associados a redução da inflamação.…”