RESUMEN
OBJECTIVE: Farnesoid X Receptor (FXR) is highly expressed in renal tubules, activation of which attenuates renal injury by suppressing inflammation and fibrosis. However, whether renal FXR contributes to the regulation of blood pressure (BP) is poorly understood. This study aimed to investigate the anti-hypertensive effect of renal FXR on high-fructose-induced salt-sensitive hypertension and underlying mechanism. METHODS: Hypertension was induced in male C57BL/6 mice by 20% fructose in drinking water with 4% sodium chloride in diet (HFS) for 8âweeks. The effects of FXR on NO production were estimated in vitro and in vivo . RESULTS: Compared with control, HFS intake elevated BP, enhanced renal injury and reduced renal NO levels as well as FXR expression in the kidney of mice. In the mouse renal collecting duct cells mIMCD-K2, FXR agonists promoted NO production by enhancing the expression of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS), whereas this effect was diminished by fxr knockdown. We further found that Dynamin 3 (DNM3), a binding protein with nNOS in the renal medulla, was inhibited by FXR and its deficiency elevated NO production in mIMCD-K2 cells. In HFS-fed mice, renal fxr overexpression significantly attenuated hypertension and renal fibrosis, regulated the expression of DNM3/nNOS/iNOS, and increased renal NO levels. CONCLUSION: Our results demonstrated that renal FXR prevents HFS-induced hypertension by inhibiting DNM3 to promote NO production. These findings provide insights into the role and potential mechanism of renal FXR for the treatment of hypertension.
Asunto(s)
Dinamina III , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Hipertensión , Animales , Dinamina III/metabolismo , Fibrosis , Fructosa/metabolismo , Fructosa/toxicidad , Hipertensión/metabolismo , Riñón , Masculino , Ratones , Ratones Endogámicos C57BL , Óxidos/metabolismo , Cloruro de Sodio , Cloruro de Sodio Dietético/efectos adversos , Cloruro de Sodio Dietético/metabolismoRESUMEN
The present study aimed to reveal the effects of immunocastration on the development of the immune system in rats. Seventy rats were randomly assigned into two groups: Control (n = 35) and immunized (n = 35). Twenty-day-old rats were immunized with gonadotropin-releasing hormone (GnRH) and booster immunization was administered every two weeks (three immunizations in total). From 20-day-old rats, we collected samples every two weeks, including five immunized rats and five control rats (seven collections in total). We collected blood samples, testicles, thymuses, and spleens. The results showed that GnRH immunization increased the GnRH antibody titers and reduced the testosterone concentration (both P < 0.05). Compared with the control group, the number of CD4+CD8- cells, CD4-CD8+ cells, and CD4+CD8+ cells increased (P < 0.05) whereas the number of CD4-CD8- cells and CD4+CD25+ cells reduced in the immunized group (P < 0.05) over time. GnRH immunization also increased the relative weights of thymus and spleen (P < 0.05), serum concentrations of interleukin (IL)-2, IL-4, IL-6, IL-10, IL-17 and Interferon-γ (IFN-γ) over time (P < 0.05), and changed the mRNA levels of IL-2, IL-4, IL-6. IL-10, IL-17, IFN-γ, CD4, D8, CD19 GnRH, and GnRH receptor (GnRH-R) in thymus and spleen. Thus, GnRH immunization enhanced the immune markers in thymus, spleen, and blood immune cytokines in rats.
Asunto(s)
Hormona Liberadora de Gonadotropina , Interleucina-10 , Ratas , Masculino , Animales , Interleucina-17 , Interleucina-4 , Interleucina-6 , Inmunización Secundaria , InmunidadRESUMEN
OBJECTIVE: Increasing studies have demonstrated that gut microbiota play vital roles in the development of hypertension. However, the underlying mechanism is not fully understood. METHODS: The relative abundance of Enterococcus faecalis was determined in the faecal samples of angiotensin II or deoxycorticosterone acetate/salt-induced hypertensive rats. Then, E. faecalis culture was administered orally to rats for 6 weeks. Blood pressure (BP) was measured, renal injury was estimated and a serum metabolomic analysis was performed. RESULTS: Compared with control, E. faecalis was markedly enriched in the faecal samples of hypertensive rats. The rats receiving live E. faecalis but not dead bacteria exhibited higher BP and enhanced renal injury. The serum metabolomic data showed that the E. faecalis treatment resulted in 35 variable metabolites including 16 (46%) lipid/lipid-like molecules, suggesting significant disturbance of lipid metabolism. Furthermore, the mRNA levels of 18 lipid metabolic enzymes in the renal medulla and cortex presented distinct and dynamic changes in response to 3 or 6-week E. faecalis treatment. Consistently, the protein levels of lysophospholipases A1 (LYPLA1) and phospholipase A2 group 4 A (PLA2G4) were enhanced only by live E. faecalis, which thus may have decreased the nitric oxide production in the renal medulla and elevated BP. CONCLUSION: Our results suggest that E. faecalis in the gut contributes to hypertension and renal injury in rats by disturbing the lipid metabolism. The information provided here could shed new light on the pathologic mechanisms and potential intervention targets for the treatment of gut dysbiosis-induced hypertension.