Pontes Roberto B, Crajoinas Renato O, Nishi Erika E, Oliveira-Sales Elizabeth B, Girardi Adriana C, Campos Ruy R, Bergamaschi Cássia T
Departamento de Fisiologia, Disciplina de Fisiologia Cardiovascular, Universidade Federal de São Paulo, São Paulo, Brazil; and.
Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil.
Am J Physiol Renal Physiol. 2015 Apr 15;308(8):F848-56. doi: 10.1152/ajprenal.00515.2014. Epub 2015 Feb 4.
Renal nerve stimulation at a low frequency (below 2 Hz) causes water and sodium reabsorption via α1-adrenoreceptor tubular activation, a process independent of changes in systemic blood pressure, renal blood flow, or glomerular filtration rate. However, the underlying mechanism of the reabsorption of sodium is not fully understood. Since the sympathetic nervous system and intrarenal ANG II appear to act synergistically to mediate the process of sodium reabsorption, we hypothesized that low-frequency acute electrical stimulation of the renal nerve (ESRN) activates NHE3-mediated sodium reabsorption via ANG II AT1 receptor activation in Wistar rats. We found that ESRN significantly increased urinary angiotensinogen excretion and renal cortical ANG II content, but not the circulating angiotensinogen levels, and also decreased urinary flow and pH and sodium excretion via mechanisms independent of alterations in creatinine clearance. Urinary cAMP excretion was reduced, as was renal cortical PKA activity. ESRN significantly increased NHE3 activity and abundance in the apical microvillar domain of the proximal tubule, decreased the ratio of phosphorylated NHE3 at serine 552/total NHE3, but did not alter total cortical NHE3 abundance. All responses mediated by ESRN were completely abolished by a losartan-mediated AT1 receptor blockade. Taken together, our results demonstrate that higher NHE3-mediated proximal tubular sodium reabsorption induced by ESRN occurs via intrarenal renin angiotensin system activation and triggering of the AT1 receptor/inhibitory G-protein signaling pathway, which leads to inhibition of cAMP formation and reduction of PKA activity.
低频（低于2Hz）肾神经刺激通过α1 - 肾上腺素能受体肾小管激活导致水和钠重吸收，这一过程独立于全身血压、肾血流量或肾小球滤过率的变化。然而，钠重吸收的潜在机制尚未完全明确。由于交感神经系统和肾内血管紧张素II似乎协同作用介导钠重吸收过程，我们推测肾神经的低频急性电刺激（ESRN）通过激活Wistar大鼠中的血管紧张素II AT1受体来激活NHE3介导的钠重吸收。我们发现，ESRN显著增加尿血管紧张素原排泄和肾皮质血管紧张素II含量，但不影响循环血管紧张素原水平，并且通过独立于肌酐清除率改变的机制降低尿流量、pH值和钠排泄。尿cAMP排泄减少，肾皮质PKA活性也降低。ESRN显著增加近端小管顶端微绒毛区域的NHE3活性和丰度，降低丝氨酸552位点磷酸化NHE3与总NHE3的比例，但不改变总皮质NHE3丰度。ESRN介导的所有反应均被氯沙坦介导的AT1受体阻断完全消除。综上所述，我们的结果表明，ESRN诱导的更高水平的NHE3介导的近端小管钠重吸收是通过肾内肾素血管紧张素系统激活以及AT1受体/抑制性G蛋白信号通路的触发而发生的，这导致cAMP形成的抑制和PKA活性的降低。
