Exogenous and endogenous angiotensin‐II decrease renal cortical oxygen tension in conscious rats by limiting renal blood flow

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 PnormalO2 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 PnormalO2; 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. AbstractWe 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 PnormalO2. The method reproducibly detected acute changes in cortical oxygenation induced by systemic hyperoxia and hypoxia. In conscious rats, renal cortical PnormalO2 was dose‐dependently reduced by intravenous AngII. Reductions in PnormalO2 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 PnormalO2. 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.

Nitric Oxide Synthase Inhibition Induces Renal Medullary Hypoxia in Conscious Rats

“…Blood gas variables in samples from the left renal vein and femoral artery were analyzed on a blood gas analyzer (GEM 4000; Instrumentation Laboratory, Bedford, MA). Kidney oxygen consumption (QO 2 , μmol/min) was calculated from the arteriovenous difference in oxygen content with a standard equation (oxygen content=[Hb]·O 2 saturation·1.34+pO 2 ·0.003) multiplied by RBF 2. At the end of the renal function measurements study, kidneys were collected, weighed, and processed for quantification of injury.…”

“…Baseline (nA) values were determined after recovery during 5 days before NOS inhibition and set at 100% (Figure 3). Artefacts were removed when the first‐order derivative exceeded a threshold of 5 nA/s, as described 2. Telemetry data, summated over 6 hours (Figure 3) and 15‐minute periods (Figure 4), are expressed as averages±SEM.…”

“…For this justification, the main goal of this study was to continuously record dynamics in renal pO 2 in both cortex and medulla in a model known for the development of kidney injury. Previously, we measured renal tissue pO 2 in the rat kidney during angiotensin‐II–induced hypertension and found a surprising contrast between acute and chronic effects 2, 3. Here, we measured oxygenation over time during deprivation of nitric oxide (NO) by NO synthase (NOS) inhibition.…”

Circadian Rhythm in Kidney Tissue Oxygenation in the Rat

“…The telemetry based technique to measure oxygenation in the kidney has been described in detail (Emans et al, 2016; Koeners et al, 2016). In summary, oxygen sensitive carbon paste electrodes were implanted in the right kidney, either in the cortex ( n = 7) or medulla ( n = 9).…”

“…Artifacts were removed when the 1st order derivative exceeded a threshold of 5 nA/s, as described previously (Emans et al, 2016). To describe the 24-h rhythm, 1 h average pO 2 -values were calculated.…”