The Renin–Angiotensin System, Not the Kinin–Kallikrein System, Affects Post-Exercise Proteinuria

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Abstract

Background/Aims: Temporary proteinuria post-exercise is common and is caused predominantly by renal haemodynamic alterations. One reason is up-regulation of angiotensin II (Ang II) due to the reducing effect of angiotensin-converting enzyme (ACE) inhibitors. However, another, ignored, reason could be the kininase effect of ACE inhibition. This study investigated how ACE inhibition reduces post-exercise proteinuria: by either Ang II up-regulation inhibition or bradykinin elevation due to kininase activity inhibition. Methods: Our study included 10 volunteers, who completed 3 high-intensity exercise protocols involving cycling at 1-week intervals. The first protocol was a control arm, the second evaluated the effect of ACE inhibition and the third examined the effect of angiotensin type 1 receptor blockade. Upon application, both agents reduced systolic and diastolic blood pressure; however, there were no statistically significant differences. In addition, total protein, microalbumin and β<sub>2</sub>-microglobulin excretion levels in urine specimens were analysed before, 30 min after and 120 min after the exercise protocols. Results: Total protein levels in urine samples were elevated in all 3 protocols after 30 min of high-intensity exercise, compared to baseline levels. However, both ACE inhibition and angiotensin type 1 receptor blockade suppressed total protein in the 30th min. In each protocol, total protein levels returned to the baseline after 120 min. Urinary microalbumin and β<sub>2</sub>-microglobulin levels during the control protocol were significantly higher 30 min post-exercise; however, only angiotensin type 1 receptor blockade suppressed microalbumin levels. Conclusion: The results indicated Ang II up-regulation, not bradykinin elevation, plays a role in post-exercise proteinuria.

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Adaptations in control of blood flow with training: splanchnic and renal blood flows.

David R. McAllister (1998)

Acute exercise is associated with large increases in cardiac and active skeletal muscle blood flows and reduced blood flows to inactive muscle, skin, kidneys, and organs served by the splanchnic circulation. Splanchnic and renal blood flows are reduced in proportion to relative exercise intensity. Increased sympathetic nervous system outflow to splanchnic and renal vasculature appears to be the primary mediator of reduced blood flows in these circulations, but the vasoconstrictors angiotensin II and vasopressin also make important contributions. Human and animal studies have shown that splanchnic and renal blood flows are reduced less from resting levels during acute exercise after a period of endurance exercise training. Investigations of mechanisms involved in these adaptations suggest that reductions in sympathetic nervous system outflow, and plasma angiotensin II and vasopressin concentrations, are involved in lesser splanchnic and renal vasoconstriction exhibited by trained individuals. In addition, a reduced response to the sympathetic neurotransmitter norepinephrine in renal vasculature may contribute to greater blood flow to the kidney during acute exercise after training. Greater splanchnic and renal blood flows during acute exercise following training are potentially beneficial in that disturbance from homeostasis would be less in the trained state. Additionally, increased splanchnic blood flow in the trained state may confer benefits for glucose metabolism during prolonged exercise.

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Angiotensin II blockade and low-protein diet produce additive therapeutic effects in experimental glomerulonephritis.

W Border, David H. Peters, Kristen N Noble (2000)

Transforming growth factor-beta (TGF-beta) overexpression plays a key role in the accumulation of extracellular matrix in acute and chronic renal diseases. Recent studies have suggested that the degree of reduction in pathological TGF-beta overexpression can be used as a therapeutic index to evaluate the antifibrotic potential of pharmacological angiotensin II (Ang II) blockade in renal disease. Using this target, we found that treatment with the angiotensin I-converting enzyme inhibitor enalapril or the Ang II type 1 receptor antagonist losartan reduced TGF-beta overexpression more effectively at doses clearly higher than those required to control blood pressure. However, both forms of Ang II blockade were only partially effective in normalizing TGF-beta expression. This study investigated whether a greater antifibrotic, TGF-beta-reducing benefit can be achieved when Ang II blockade is combined with dietary protein restriction. Mesangioproliferative glomerulonephritis was induced in male Sprague-Dawley rats on a normal-protein diet. Treatment with a low-protein diet and/or maximally effective doses of enalapril or losartan was started one day after disease induction. On the fifth day, 24-hour urine protein excretion was measured. On the sixth day, cortical kidney tissue was taken for periodic acid-Schiff staining. Isolated glomeruli were used for mRNA extraction or were placed in culture for determination of production of TGF-beta1, the matrix protein fibronectin, and the protease inhibitor plasmin activator inhibitor type 1 (PAI-1) by enzyme-linked immunosorbent assay. Compared with untreated nephritic animals on a normal-protein diet, a single treatment with enalapril, losartan, or low-protein diet significantly reduced glomerular TGF-beta production, albeit to a similar degree of approximately 45%. A moderate, but significant further reduction in pathological TGF-beta expression of a total of 65% for enalapril and 60% for losartan was achieved when these drugs were combined with low-protein feeding. This reduction in TGF-beta overexpression paralleled decreased proteinuria, glomerular matrix accumulation, and overproduction of fibronectin and PAI-1. Ang II blockade and low-protein diet have additive effects on disease reduction, suggesting that disease progression in humans with chronic renal failure may be slowed more effectively when Ang II blockade and low-protein diet are combined. Since maximal pharmacological Ang II inhibition was used, it is likely that dietary protein restriction further reduces pathological TGF-beta overexpression by mechanisms different from those of enalapril or losartan.

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Pharmacological blockade of B2-kinin receptor reduces renal protective effect of angiotensin-converting enzyme inhibition in db/db mice model.

Zara Dickson, Françoise Praddaude, Christiane Pecher … (2008)

Diabetic nephropathy (DN) can be delayed by the use of angiotensin-converting enzyme inhibitors (ACEi). The mechanisms of ACEi renal protection are not univocal. To investigate the impact of bradykinin B(2) receptor (B2R) activation during ACE inhibition, type II diabetic mice (C57BLKS db/db) received for 20 wk: 1) ACEi (ramipril) alone, 2) ACEi + HOE-140 (a specific B2R antagonist), 3) HOE-140 alone, or 4) no treatment. The development of DN, defined by an increase in albuminuria and glomerulosclerosis, was largely prevented by ACEi treatment (albuminuria: 980 +/- 130 vs. 2,160 +/- 330 mg/g creatinine; mesangial area: 22.5 +/- 0.5 vs. 27.6 +/- 0.3%). The protective effect of ramipril was markedly attenuated by B2R blockade (albuminuria: 2,790 +/- 680 mg/g creatinine; mesangial area: 30.4 +/- 1.1%), whereas HOE-140 alone significantly increased albuminuria. Despite such benefits, glomerular filtration rate remained unchanged, probably because of the combination of the hypotensive effect of diabetes in this model and the renal hemodynamic action of ramipril. Finally, the renal protective effect of ACEi was associated with a marked decrease in glomerular overexpression of insulin-like growth factor-1 (IGF-1) and transforming growth factor-beta pathways, but also in advanced glycation end product receptors and lipid peroxidation assessed by 4-hydroxy-2-nonenal (4-HNE) adducts. Concomitant blockade of B2R partly restored glomerular overexpression of IGF-1 receptor beta and 4-HNE complexes. These results support the critical role of B2R activation in the mediation of ACEi renal protection against DN and provide the rationale to examine the benefit of B2R activation by itself as a new therapeutic approach for DN.

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Author and article information

Journal

Journal ID (publisher-id): NEF

Journal ID (nlm-ta): Nephron

Journal ID (doi): 10.1159/issn.1660-8151

Title: Nephron

Publisher: S. Karger AG

ISSN (Print): 1660-8151

ISSN (Electronic): 2235-3186

Publication date Subscription-year: 2018

Publication date (Print): July 2018

Publication date (Electronic): 17 May 2018

Volume: 139

Issue: 4

Pages: 299-304

Affiliations

[_a] _aDepartment of Physiology, Near East University, Medical Faculty, Nicosia, Cyprus

[_b] _bDepartment of Physiology, Akdeniz University, Medical Faculty, Antalya, Turkey

[_c] _cDepartment of Physical Therapy and Rehabilitation, Muğla Sıtkı Koçman University, Faculty of Health Sciences, Muğla, Turkey

Author notes

*Prof. Ümit Kemal Şentürk, Department of Physiology, Akdeniz University, Medical Faculty, Kampus, TR–07070 Antalya (Turkey), E-Mail uksenturk@akdeniz.edu.tr

Article

Publisher ID: 489506 Other ID: Nephron 2018;139:299–304

DOI: 10.1159/000489506

PubMed ID: 29772567

SO-VID: 4e4b7e60-a0e0-4705-b04b-d61ba5599439

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 13 November 2017

Date accepted : 22 April 2018

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Figures: 3, Tables: 2, Pages: 6

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The Renin–Angiotensin System, Not the Kinin–Kallikrein System, Affects Post-Exercise Proteinuria

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Karger: Nephrology

Most cited references 21

Adaptations in control of blood flow with training: splanchnic and renal blood flows.

Angiotensin II blockade and low-protein diet produce additive therapeutic effects in experimental glomerulonephritis.

Pharmacological blockade of B2-kinin receptor reduces renal protective effect of angiotensin-converting enzyme inhibition in db/db mice model.

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