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      Angiotensin II Blockade Augments Renal Cortical Microvascular pO 2 Indicating a Novel, Potentially Renoprotective Action

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          Background: The existence of tubulointerstitial damage in most cases of progressive human glomerular disease suggests that this compartment of the kidney is likely to be targeted by renoprotective agents which slow the progression of disease. Angiotensin-converting enzyme (ACE) inhibitors have become the cornerstone of renal protection. Since we have proposed that perturbation of the interstitial capillary circulation with consequent chronic hypoxia could be critical to the progressive nature of many renal diseases, we developed a dynamic method of measuring renal cortical pO<sub>2</sub> and sought to determine whether agents which block the renal effects of angiotensin II (AII) could affect interstitial microvascular oxygenation in the normal rat kidney. Methods: Instrumented, anaesthetised adult male Sprague-Dawley rats were studied. Cortical microvascular pO<sub>2 </sub>was measured on the surface of the exposed kidney using protoporphyrin phosphorescence. Blood pressure and renal artery blood flow (Doppler flowmetry) were measured concurrently over a 180-min experimental period. Animals received non-hypotensive doses of enalaprilat (100 µg/kg i.v.) or candesartan (40 µg/kg i.v.) either at the beginning of the experimental period or after an initial decline in cortical microvascular pO<sub>2</sub>. Results: After a 30-min stabilisation period there was a slow decline in pO<sub>2 </sub>from 48.6 ± 4.1 to 38.5 ± 6.9 mm Hg in control animals over the 180-min experimental period. Administration of the ACE inhibitor, enalaprilat at the beginning of the experimental period, completely abrogated this decline and protected pO<sub>2</sub> levels throughout this period with no effect on blood pressure or renal blood flow. In separate experiments, administration of enalaprilat after microvascular pO<sub>2</sub> had fallen by 5 mm Hg, resulted in a rise in RBF and pO<sub>2 </sub>within 15 min with pO<sub>2</sub> remaining elevated for up to 60 min post-injection. The angiotensin II AT<sub>1</sub> receptor antagonist, candesartan, had a similar effect to enalaprilat, inducing a rapid and sustained elevation in cortical pO<sub>2</sub>. Conclusions: These studies indicate that blockade of AII raises pO<sub>2 </sub>in the interstitial microvascular compartment of the normal rat kidney. This effect may contribute to the renoprotective action of ACE inhibitors and AII receptor antagonists in slowing the progression of chronic renal diseases.

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          Hypoxia promotes fibrogenesis in human renal fibroblasts.

          The mechanisms underlying progressive renal fibrosis are unknown, but the common association of fibrosis and microvascular loss suggests that hypoxia per se may be a fibrogenic stimulus. To determine whether human renal fibroblasts (HRFs), the primary matrix-producing cells in the tubulointerstitium, possess oxygen-sensitive responses relevant to fibrogenesis, cells were exposed to 1% O2 in vitro. Hypoxia simultaneously stimulated extracellular matrix synthesis and suppressed turnover with increased production of collagen alpha1(I) (Coll-I), decreased expression of collagenase, and increased tissue inhibitor of metalloproteinase (TIMP)-1. These effects are time dependent, require new RNA and protein synthesis, and are specific to hypoxia. The changes in Coll-I and TIMP-1 gene expression involve a heme-protein O2 sensor and protein kinase- and tyrosine kinase-mediated signaling. Although hypoxia induced transforming growth factor-beta1 (TGF-beta1), neutralizing anti-TGF-beta1-antibody did not block hypoxia-induced Coll-I and TIMP-1 mRNA expression. Furthermore, hypoxic-cell conditioned-medium had no effect on the expression of these mRNAs in naive fibroblasts, suggesting direct effects on gene transcription. Transient transfections identified a hypoxia response element (HRE) in the TIMP-1 promoter and demonstrated HIF-1-dependent promoter activation by decreased ambient pO2. These data suggest that hypoxia co-ordinately up-regulates matrix production and decreases turnover in renal fibroblasts. The results support a role for hypoxia in the pathogenesis of fibrosis and provide evidence for novel, direct hypoxic effects on the expression of genes involved in fibrogenesis.
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            Renal oxygenation defects in the spontaneously hypertensive rat: role of AT1 receptors.

            The spontaneously hypertensive rat (SHR) has oxidative stress and enhanced O2 usage (Q(O2)) relative to tubular sodium transport (TNa). Angiotensin II (Ang II) acting on Type I receptors (AT1-R) causes renal oxidative stress and functional nitric oxide (NO) deficiency that could enhance O2 usage. Therefore, we investigated the hypothesis that AT1-Rs mediate the inefficient renal oxygenation in the SHR.
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              Intravenous crocetinate prolongs survival in a rat model of lethal hypoxemia


                Author and article information

                Nephron Physiol
                Nephron Physiology
                S. Karger AG
                June 2003
                04 July 2003
                : 94
                : 2
                : p39-p46
                Centres for aNephrology and bIntensive Care Medicine, Department of Medicine, Royal Free and University College Medical School, London, UK
                71289 Nephron Physiol 2003;94:p39–p46
                © 2003 S. Karger AG, Basel

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                Figures: 5, References: 24, Pages: 1
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