Emans Tonja W, Janssen Ben J, Pinkham Maximilian I, Ow Connie P C, Evans Roger G, Joles Jaap A, Malpas Simon C, Krediet C T Paul, Koeners Maarten P
Nephrology and Hypertension, University Medical Centre Utrecht, Utrecht, The Netherlands.
Internal Medicine-Nephrology, Academic Medical Centre at the University of Amsterdam, The Netherlands.
J Physiol. 2016 Nov 1;594(21):6287-6300. doi: 10.1113/JP270731. Epub 2016 Aug 18.
Our understanding of the mechanisms underlying the role of hypoxia in the initiation and progression of renal disease remains rudimentary. We have developed a method that allows wireless measurement of renal tissue oxygen tension in unrestrained rats. This method provides stable and continuous measurements of cortical tissue oxygen tension (PO2) for more than 2 weeks and can reproducibly detect acute changes in cortical oxygenation. Exogenous angiotensin-II reduced renal cortical tissue PO2 more than equi-pressor doses of phenylephrine, probably because it reduced renal oxygen delivery more than did phenylephrine. Activation of the endogenous renin-angiotensin system in transgenic Cyp1a1Ren2 rats reduced cortical tissue PO2; in this model renal hypoxia precedes the development of structural pathology and can be reversed acutely by an angiotensin-II receptor type 1 antagonist. Angiotensin-II promotes renal hypoxia, which may in turn contribute to its pathological effects during development of chronic kidney disease.
We hypothesised that both exogenous and endogenous angiotensin-II (AngII) can decrease the partial pressure of oxygen (PO2) in the renal cortex of unrestrained rats, which might in turn contribute to the progression of chronic kidney disease. Rats were instrumented with telemeters equipped with a carbon paste electrode for continuous measurement of renal cortical tissue PO2. The method reproducibly detected acute changes in cortical oxygenation induced by systemic hyperoxia and hypoxia. In conscious rats, renal cortical PO2 was dose-dependently reduced by intravenous AngII. Reductions in PO2 were significantly greater than those induced by equi-pressor doses of phenylephrine. In anaesthetised rats, renal oxygen consumption was not affected, and filtration fraction was increased only in the AngII infused animals. Oxygen delivery decreased by 50% after infusion of AngII and renal blood flow (RBF) fell by 3.3 ml min . Equi-pressor infusion of phenylephrine did not significantly reduce RBF or renal oxygen delivery. Activation of the endogenous renin-angiotensin system in Cyp1a1Ren2 transgenic rats reduced cortical tissue PO2. This could be reversed within minutes by pharmacological angiotensin-II receptor type 1 (AT R) blockade. Thus AngII is an important modulator of renal cortical oxygenation via AT receptors. AngII had a greater influence on cortical oxygenation than did phenylephrine. This phenomenon appears to be attributable to the profound impact of AngII on renal oxygen delivery. We conclude that the ability of AngII to promote renal cortical hypoxia may contribute to its influence on initiation and progression of chronic kidney disease.
我们对缺氧在肾脏疾病发生和发展中作用的潜在机制的理解仍很初步。我们开发了一种方法，可对自由活动的大鼠的肾组织氧张力进行无线测量。该方法能对皮质组织氧张力（PO₂）进行稳定且连续超过2周的测量，并能重复检测皮质氧合的急性变化。外源性血管紧张素II降低肾皮质组织PO₂的作用比等剂量升压的去氧肾上腺素更强，这可能是因为它比去氧肾上腺素更能降低肾脏的氧输送。转基因Cyp1a1Ren2大鼠体内内源性肾素-血管紧张素系统的激活降低了皮质组织PO₂；在该模型中，肾脏缺氧先于结构病理学的发展，且可被1型血管紧张素II受体拮抗剂迅速逆转。血管紧张素II促进肾脏缺氧，这反过来可能在慢性肾脏病发展过程中促成其病理作用。
我们假设外源性和内源性血管紧张素II（AngII）均可降低自由活动大鼠肾皮质中的氧分压（PO₂），这反过来可能促成慢性肾脏病的进展。给大鼠植入配备碳糊电极的遥测仪，以连续测量肾皮质组织PO₂。该方法能重复检测由全身高氧和缺氧诱导的皮质氧合急性变化。在清醒大鼠中，静脉注射AngII可使肾皮质PO₂呈剂量依赖性降低。PO₂的降低显著大于等剂量升压的去氧肾上腺素所诱导的降低。在麻醉大鼠中，肾脏氧消耗不受影响，仅在输注AngII的动物中滤过分数增加。输注AngII后氧输送降低50%，肾血流量（RBF）下降3.3 ml/min。等剂量升压输注去氧肾上腺素未显著降低RBF或肾脏氧输送。Cyp1a1Ren2转基因大鼠体内内源性肾素-血管紧张素系统的激活降低了皮质组织PO₂。通过药理学方法阻断1型血管紧张素II受体（AT₁R）可在数分钟内逆转这种情况。因此，AngII是通过AT₁受体对肾皮质氧合的重要调节因子。AngII对皮质氧合的影响比去氧肾上腺素更大。这种现象似乎归因于AngII对肾脏氧输送的深远影响。我们得出结论，AngII促进肾皮质缺氧的能力可能促成其对慢性肾脏病发生和发展的影响。
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