Abstract
Key points 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−1. 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 (AT1R) blockade. Thus AngII is an important modulator of renal cortical oxygenation via AT1 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.
Highlights
Chronic kidney disease (CKD) is associated with low tissue oxygen tension (PO2) within the kidney (Evans et al 2013)
The results of this study show that, in conscious unrestrained rats, renal cortical oxygen tension is decreased by stimulation of the AngII type 1 receptor (AT1R) by both exogenous and endogenous AngII
Using devices for telemetric measurement of tissue PO2, we show for the first time in conscious unrestrained rats that acute renal cortical hypoxia induced by exogenous AngII is (1) greater than that evoked by equi-pressor doses of phenylephrine; and (2) is mainly caused by reduced renal blood flow (RBF) rather than by increased oxygen consumption
Summary
Chronic kidney disease (CKD) is associated with low tissue oxygen tension (PO2) within the kidney (i.e. renal hypoxia) (Evans et al 2013). RAS inhibition has been found to improve cortical tissue oxygenation in anaesthetised rats both with (Welch et al 2003; Manotham et al 2004; Eckardt et al 2005) and without (Norman et al 2003) kidney disease These studies were performed in an acute setting in animals under anaesthesia, their findings suggest that AngII can chronically have a negative impact on renal cortical oxygenation, which could potentially be a critical factor in the initiation and progression of CKD. Consistent with this concept, angiotensin-converting enzyme inhibitors and AT1R blockade are still used as first-line treatment in patients with CKD who do not require dialysis, and have been shown to improve survival (Qin et al 2016)
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