Custódio Augusto H, de Lima Marcelo C, Vaccari Bárbara, Boer Patrícia A, Gontijo José A R
Department of Internal Medicine Faculty of Medical Science, State University of Campinas, Campinas, SP, Brazil.
PLoS One. 2017 Jun 20;12(6):e0179499. doi: 10.1371/journal.pone.0179499. eCollection 2017.
Considering long-term changes in renal sodium handling and blood pressure in maternal protein-restricted (LP) offspring, we assumed that the development of LP hypertension results from abnormal dorsal root ganglia (DRG) neurokinin expression associated with impaired responsiveness of renal sensory receptors, promoting a reduced urinary excretion of sodium. The present study investigates whether increased blood pressure in protein-restricted offspring would be associated with changes in the DRG cells and in renal pelvic wall expression of NK1R, SP and CGRP when compared to NP offspring. In addition, we assessed the tubular sodium handling, estimated by creatinine and lithium clearances before and after bilateral renal denervation in conscious LP offspring relative to age-matched NP counterparts.
Dams received a normal (NP) or low-protein diet (LP) during their entire pregnancy period. Male NP or LP offspring underwent bilateral surgical renal denervation before the 8-week renal functional test and blood pressure measurements. Immunofluorescence staining in DRG cells was assessed in optical sections by confocal laser scanning microscope.
The current data demonstrated a sustained rise in blood pressure associated with a decrease in fractional excretion of sodium (FENa) by reducing post-proximal tubule sodium rejection in 16-wk old LP rats relative to age-matched NP counterparts. According to this study, bilateral renal denervation attenuated blood pressure and increased FENa in LP offspring. Furthermore, an immunohistochemical analysis showed a reduced expression of SP and CGRP in DRGs of LP when compared with NP rats. Renal pelvis of LP rats did not show a strong CGRP expression related to NP rats, whereas there was no change in SP immunostaining.
These observations raise the possibility that impaired DRG and pelvic neurokinin expression associated with responsiveness of renal sensory receptors in 16-wk old LP offspring are conducive to excess renal reabsorption of sodium and development of hypertension in this programmed model.
考虑到母体蛋白质限制(LP)后代肾脏钠处理和血压的长期变化,我们推测LP高血压的发生是由于背根神经节(DRG)神经激肽表达异常,与肾脏感觉受体反应性受损有关,从而导致尿钠排泄减少。本研究调查了与正常蛋白质饮食(NP)后代相比,蛋白质限制后代血压升高是否与DRG细胞以及肾盂壁中神经激肽1受体(NK1R)、P物质(SP)和降钙素基因相关肽(CGRP)的表达变化有关。此外,我们评估了清醒的LP后代相对于年龄匹配的NP后代在双侧肾去神经前后通过肌酐和锂清除率估算的肾小管钠处理情况。
母鼠在整个孕期接受正常(NP)或低蛋白饮食(LP)。雄性NP或LP后代在进行8周肾功能测试和血压测量之前接受双侧手术肾去神经。通过共聚焦激光扫描显微镜在光学切片中评估DRG细胞中的免疫荧光染色。
当前数据表明,与年龄匹配的NP大鼠相比,16周龄LP大鼠血压持续升高,同时近端小管后段钠重吸收减少,导致钠排泄分数(FENa)降低。根据本研究,双侧肾去神经可降低LP后代的血压并增加FENa。此外,免疫组织化学分析显示,与NP大鼠相比,LP大鼠DRG中SP和CGRP的表达降低。LP大鼠的肾盂与NP大鼠相比未显示出与NP大鼠相关的强烈CGRP表达,而SP免疫染色没有变化。
这些观察结果提示,在这个程序化模型中,16周龄LP后代中DRG和肾盂神经激肽表达受损与肾脏感觉受体反应性相关,这有利于肾脏对钠的过度重吸收和高血压的发展。