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      Imbalance in Renal Vasoactive Enzymes Induced by Mild Hypoxia: Angiotensin-Converting Enzyme Increases While Neutral Endopeptidase Decreases

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          Abstract

          Chronic hypoxia has been postulated as one of the mechanisms involved in salt-sensitive hypertension and chronic kidney disease (CKD). Kidneys have a critical role in the regulation of arterial blood pressure through vasoactive systems, such as the renin-angiotensin and the kallikrein–kinin systems, with the angiotensin-converting enzyme (ACE) and kallikrein being two of the main enzymes that produce angiotensin II and bradykinin, respectively. Neutral endopeptidase 24.11 or neprilysin is another enzyme that among its functions degrade vasoactive peptides including angiotensin II and bradykinin, and generate angiotensin 1–7. On the other hand, the kidneys are vulnerable to hypoxic injury due to the active electrolyte transportation that requires a high oxygen consumption; however, the oxygen supply is limited in the medullary regions for anatomical reasons. With the hypothesis that the chronic reduction of oxygen under normobaric conditions would impact renal vasoactive enzyme components and, therefore; alter the normal balance of the vasoactive systems, we exposed male Sprague-Dawley rats to normobaric hypoxia (10% O 2) for 2 weeks. We then processed renal tissue to identify the expression and distribution of kallikrein, ACE and neutral endopeptidase 24.11 as well as markers of kidney damage. We found that chronic hypoxia produced focal damage in the kidney, mainly in the cortico-medullary region, and increased the expression of osteopontin. Moreover, we observed an increase of ACE protein in the brush border of proximal tubules at the outer medullary region, with increased mRNA levels. Kallikrein abundance did not change significantly with hypoxia, but a tendency toward reduction was observed at protein and mRNA levels. Neutral endopeptidase 24.11 was localized in proximal tubules, and was abundantly expressed under normoxic conditions, which markedly decreased both at protein and mRNA levels with chronic hypoxia. Taken together, our results suggest that chronic hypoxia produces focal kidney damage along with an imbalance of key components of the renal vasoactive system, which could be the initial steps for a long-term contribution to salt-sensitive hypertension and CKD.

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          Most cited references66

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          Hypoxemia in patients with COPD: cause, effects, and disease progression

          Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability internationally. Alveolar hypoxia and consequent hypoxemia increase in prevalence as disease severity increases. Ventilation/perfusion mismatch resulting from progressive airflow limitation and emphysema is the key driver of this hypoxia, which may be exacerbated by sleep and exercise. Uncorrected chronic hypoxemia is associated with the development of adverse sequelae of COPD, including pulmonary hypertension, secondary polycythemia, systemic inflammation, and skeletal muscle dysfunction. A combination of these factors leads to diminished quality of life, reduced exercise tolerance, increased risk of cardiovascular morbidity, and greater risk of death. Concomitant sleep-disordered breathing may place a small but significant subset of COPD patients at increased risk of these complications. Long-term oxygen therapy has been shown to improve pulmonary hemodynamics, reduce erythrocytosis, and improve survival in selected patients with severe hypoxemic respiratory failure. However, the optimal treatment for patients with exertional oxyhemoglobin desaturation, isolated nocturnal hypoxemia, or mild-to-moderate resting daytime hypoxemia remains uncertain.
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            Acute SGLT inhibition normalizes O2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats.

            Early stage diabetic nephropathy is characterized by glomerular hyperfiltration and reduced renal tissue Po2. Recent observations have indicated that increased tubular Na(+)-glucose linked transport (SGLT) plays a role in the development of diabetes-induced hyperfiltration. The aim of the present study was to determine how inhibition of SLGT impacts upon Po2 in the diabetic rat kidney. Diabetes was induced by streptozotocin in Sprague-Dawley rats 2 wk before experimentation. Renal hemodynamics, excretory function, and renal O2 homeostasis were measured in anesthetized control and diabetic rats during baseline and after acute SGLT inhibition using phlorizin (200 mg/kg ip). Baseline arterial pressure was similar in both groups and unaffected by SGLT inhibition. Diabetic animals displayed reduced baseline Po2 in both the cortex and medulla. SGLT inhibition improved cortical Po2 in the diabetic kidney, whereas it reduced medullary Po2 in both groups. SGLT inhibition reduced Na(+) transport efficiency [tubular Na(+) transport (TNa)/renal O2 consumption (Qo2)] in the control kidney, whereas the already reduced TNa/Qo2 in the diabetic kidney was unaffected by SGLT inhibition. In conclusion, these data demonstrate that when SGLT is inhibited, renal cortex Po2 in the diabetic rat kidney is normalized, which implies that increased proximal tubule transport contributes to the development of hypoxia in the diabetic kidney. The reduction in medullary Po2 in both control and diabetic kidneys during the inhibition of proximal Na(+) reabsorption suggests the redistribution of active Na(+) transport to less efficient nephron segments, such as the medullary thick ascending limb, which results in medullary hypoxia.
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              The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment

              This article overviews the natriuretic peptides (NPs) system, its role and the development of NP-based treatment of heart failure (HF).
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                11 December 2018
                2018
                : 9
                : 1791
                Affiliations
                [1] 1Department of Physiology, Center for Aging and Regeneration CARE UC, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile , Santiago, Chile
                [2] 2Facultad de Medicina y Ciencia, Universidad San Sebastián , Santiago, Chile
                [3] 3Institute of Anatomy, Histology, and Pathology, Facultad de Medicina, Universidad Austral de Chile , Valdivia, Chile
                [4] 4Laboratorio de Fisiología Celular, Departamento de Biología, Facultad de Ciencias, Universidad de Chile , Santiago, Chile
                [5] 5Laboratorio de Neurobiología, Department of Physiology, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile , Santiago, Chile
                Author notes

                Edited by: Ovidiu Constantin Baltatu, Anhembi Morumbi University, Brazil

                Reviewed by: Zaid A. Abassi, Technion – Israel Institute of Technology, Israel; Manuel Ramírez-Sánchez, Universidad de Jaén, Spain; Beth J. Allison, Hudson Institute of Medical Research, Australia

                *Correspondence: Carlos P. Vio, cvio@ 123456uc.cl

                This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2018.01791
                6297360
                f83b26c5-5a5c-452f-80d8-71b4756e0b11
                Copyright © 2018 Vio, Salas, Cespedes, Diaz-Elizondo, Mendez, Alcayaga and Iturriaga.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 28 June 2018
                : 28 November 2018
                Page count
                Figures: 10, Tables: 1, Equations: 0, References: 70, Pages: 14, Words: 0
                Funding
                Funded by: Comisión Nacional de Investigación Científica y Tecnológica 10.13039/501100002848
                Funded by: Fondo Nacional de Desarrollo Científico y Tecnológico 10.13039/501100002850
                Categories
                Physiology
                Original Research

                Anatomy & Physiology
                renal hypoxia,kallikrein,angiotensin-converting enzyme,neprilysin,neutral endopeptidase,subtle renal injury

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