CoChat
Sign Up
Cited by 23Diabetes Treatment and ManagementChronic Kidney Disease and DiabetesRenin-Angiotensin System Studies

GLP−1 Promotes Cortical and Medullary Perfusion in the Human Kidney and Maintains Renal Oxygenation During NaCl Loading

Open access
Haddock, Bryan, Kristensen, Kasper B., Tayyab, Mahvish, Larsson, Henrik B. W., Lindberg, Ulrich, Vestergaard, Mark, Francis, Susan, Jensen, Boye L. +2 more·2023·Journal of the American Heart Association
DOI 10.1161/jaha.122.027712PMC PMC9973647
Open this paper in CoChat — free accountOpen PDF

Abstract

Background: GLP‐1 (glucagon‐like peptide‐1) receptor agonists exert beneficial long‐term effects on cardiovascular and renal outcomes. In humans, the natriuretic effect of GLP‐1 depends on GLP‐1 receptor interaction, is accompanied by suppression of angiotensin II, and is independent of changes in renal plasma flow. In rodents, angiotensin II constricts vasa recta and lowers medullary perfusion. The current randomized, controlled, crossover study was designed to test the hypothesis that GLP‐1 increases renal medullary perfusion in healthy humans. Methods and Results: Healthy male participants (n=10, aged 27±4 years) ingested a fixed sodium intake for 4 days and were examined twice during a 1‐hour infusion of either GLP‐1 (1.5 pmol/kg per minute) or placebo together with infusion of 0.9% NaCl (750 mL/h). Interleaved measurements of renal arterial blood flow, oxygenation (R 2 *), and perfusion were acquired in the renal cortex and medulla during infusions, using magnetic resonance imaging. GLP‐1 infusion increased medullary perfusion (32±7%, P <0.001) and cortical perfusion (13±4%, P <0.001) compared with placebo. Here, NaCl infusion decreased medullary perfusion (−5±2%, P =0.007), whereas cortical perfusion remained unchanged. R 2 * values increased by 3±2% ( P =0.025) in the medulla and 4±1% ( P =0.008) in the cortex during placebo, indicative of decreased oxygenation, but remained unchanged during GLP‐1. Blood flow in the renal artery was not altered significantly by either intervention. Conclusions: GLP‐1 increases predominantly medullary but also cortical perfusion in the healthy human kidney and maintains renal oxygenation during NaCl loading. In perspective, suppression of angiotensin II by GLP‐1 may account for the increase in regional perfusion. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04337268.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1161/jaha.122.027712

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 44 · Cited by 23

Research works printed but not linked: 37

  1. [3]Muskiet MHA, Tonneijck L, Smits MM, van Baar MJB, Kramer MHH, Hoorn EJ, Joles JA, van Raalte DH. GLP‐1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat Rev Nephrol. 2017; 13: 605– 628. doi: 10.1038/nrneph.2017.123 28869249 · DOI · Paper page
  2. [4]Gutzwiller J‐P, Tschopp S, Bock A, Zehnder CE, Huber AR, Kreyenbuehl M, Gutmann H, Drewe J, Henzen C, Goeke B, et al. Glucagon‐like peptide 1 induces natriuresis in healthy subjects and in insulin‐resistant obese men. J Clin Endocrinol Metab. 2004; 89: 3055– 3061. doi: 10.1210/jc.2003-031403 15181098 · DOI · Paper page
  3. [5]Asmar A, Cramon PK, Simonsen L, Asmar M, Sorensen CM, Madsbad S, Moro C, Hartmann B, Jensen BL, Holst JJ, et al. Extracellular fluid volume expansion uncovers a natriuretic action of GLP‐1: a functional GLP‐1‐renal axis in man. J Clin Endocrinol Metab. 2019; 104: 2509– 2519. doi: 10.1210/jc.2019-00004 30835273 · DOI
  4. [6]Asmar A, Cramon PK, Asmar M, Simonsen L, Sorensen CM, Madsbad S, Hartmann B, Holst JJ, Hovind P, Jensen BL, et al. The renal extraction and the natriuretic action of GLP‐1 in humans depend on interaction with the GLP‐1 receptor. J Clin Endocrinol Metab. 2021; 106: e11– e19. doi: 10.1210/clinem/dgaa643 32927478 · DOI
  5. [7]Muskiet MHA, Tonneijck L, Smits MM, Kramer MHH, Diamant M, Joles JA, van Raalte DH. Acute renal haemodynamic effects of glucagon‐like peptide‐1 receptor agonist exenatide in healthy overweight men. Diabetes Obes Metab. 2016; 18: 178– 185. doi: 10.1111/dom.12601 26636423 · DOI · Paper page
  6. [8]Tonneijck L, Smits MM, Muskiet MHA, Hoekstra T, Kramer MHH, Danser AHJ, Diamant M, Joles JA, van Raalte DH. Acute renal effects of the GLP‐1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double‐blind, placebo‐controlled trial. Diabetologia. 2016; 59: 1412– 1421. doi: 10.1007/s00125-016-3938-z 27038451 PMC4901099 · DOI · Paper page
  7. [11]Asmar A, Simonsen L, Asmar M, Madsbad S, Holst JJ, Frandsen E, Moro C, Jonassen T, Bülow J. Renal extraction and acute effects of glucagon‐like peptide‐1 on central and renal hemodynamics in healthy men. Am J Physiol Endocrinol Metab. 2015; 308: E641– E649. doi: 10.1152/ajpendo.00429.2014 25670826 · DOI
  8. [12]Edwards RM. Segmental effects of norepinephrine and angiotensin II on isolated renal microvessels. Am J Physiol. 1983; 244: F526– F534. doi: 10.1152/ajprenal.1983.244.5.F526 6846541 · DOI
  9. [13]Pallone TL. Vasoconstriction of outer medullary vasa recta by angiotensin II is modulated by prostaglandin E2. Am J Physiol. 1994; 266: F850– F857. doi: 10.1152/ajprenal.1994.266.6.F850 8023965 · DOI
  10. [14]Cupples WA, Sakai T, Marsh DJ. Angiotensin II and prostaglandins in control of vasa recta blood flow. Am J Physiol. 1988; 254: F417– F424. doi: 10.1152/ajprenal.1988.254.3.F417 3279819 · DOI
  11. [15]Pallone TL, Robertson CR, Jamison RL. Renal medullary microcirculation. Physiol Rev. 1990; 70: 885– 920. doi: 10.1152/physrev.1990.70.3.885 2194225 · DOI
  12. [16]Asmar A, Simonsen L, Asmar M, Madsbad S, Holst JJ, Frandsen E, Moro C, Sorensen CM, Jonassen T, Bülow J. Glucagon‐like peptide‐1 does not have acute effects on central or renal hemodynamics in patients with type 2 diabetes without nephropathy. Am J Physiol Endocrinol Metab. 2016; 310: E744– E753. doi: 10.1152/ajpendo.00518.2015 26956188 · DOI
  13. [17]Asmar A, Asmar M, Simonsen L, Madsbad S, Holst JJ, Hartmann B, Sorensen CM, Bülow J. Glucagon‐like peptide‐1 elicits vasodilation in adipose tissue and skeletal muscle in healthy men. Physiol Rep. 2017; 5: e13073. doi: 10.14814/phy2.13073 28174344 PMC5309569 · DOI
  14. [18]Nery F, Buchanan CE, Harteveld AA, Odudu A, Bane O, Cox EF, Derlin K, Gach HM, Golay X, Gutberlet M. Consensus‐based technical recommendations for clinical translation of renal ASL MRI. MAGMA. 2020; 33: 141– 161. doi: 10.1007/s10334-019-00800-z 31833014 PMC7021752 · DOI
  15. [19]Dekkers IA, de Boer A, Sharma K, Cox EF, Lamb HJ, Buckley DL, Bane O, Morris DM, Prasad PV, Semple SIK. Consensus‐based technical recommendations for clinical translation of renal T1 and T2 mapping MRI. MAGMA. 2020; 33: 163– 176. doi: 10.1007/s10334-019-00797-5 31758418 PMC7021750 · DOI
  16. [20]Haddock BT, Francis ST, Larsson HBW, Andersen UB. Assessment of perfusion and oxygenation of the human renal cortex and medulla by quantitative MRI during handgrip exercise. J Am Soc Nephrol. 2018; 29: 2510– 2517. doi: 10.1681/ASN.2018030272 30206141 PMC6171273 · DOI
  17. [21]Haddock B, Larsson HBW, Francis S, Andersen UB. Human renal response to furosemide: simultaneous oxygenation and perfusion measurements in cortex and medulla. Acta Physiol (Oxf). 2019; 227: e13292. doi: 10.1111/apha.13292 31046189 PMC6767552 · DOI
  18. [22]Cox EF, Buchanan CE, Bradley CR, Prestwich B, Mahmoud H, Taal M, Selby NM, Francis ST. Multiparametric renal magnetic resonance imaging: validation, interventions, and alterations in chronic kidney disease. Front Physiol. 2017; 8: 696. doi: 10.3389/fphys.2017.00696 28959212 PMC5603702 · DOI
  19. [23]Gardener AG, Francis ST. Multislice perfusion of the kidneys using parallel imaging: image acquisition and analysis strategies. Magn Reson Med. 2010; 63: 1627– 1636. doi: 10.1002/mrm.22387 20512866 · DOI
  20. [24]Karger N, Biederer J, Lüsse S, Grimm J, Steffens J, Heller M, Glüer C. Quantitation of renal perfusion using arterial spin labeling with FAIR‐UFLARE. Magn Reson Imaging. 2000; 18: 641– 647. doi: 10.1016/S0730-725X(00)00155-7 10930773 · DOI
  21. [25]de Boer A, Villa G, Bane O, Bock M, Cox EF, Dekkers IA, Eckerbom P, Fernández‐Seara MA, Francis ST, Haddock B. Consensus‐based technical recommendations for clinical translation of renal phase contrast MRI. J Magn Reson Imaging. 2022; 55: 323– 335. doi: 10.1002/jmri.27419 33140551 PMC9291014 · DOI
  22. [26]Hansell P, Welch WJ, Blantz RC, Palm F. Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension. Clin Exp Pharmacol Physiol. 2013; 40: 123– 137. doi: 10.1111/1440-1681.12034 23181475 PMC3951849 · DOI · Paper page
  23. [27]Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double‐blind crossover study on the effects of 2‐L infusions of 0.9% saline and plasma‐lyte® 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg. 2012; 256: 18– 24. doi: 10.1097/SLA.0b013e318256be72 22580944 · DOI · Paper page
  24. [28]Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double‐blind crossover study on the effects of 1‐L infusions of 6% hydroxyethyl starch suspended in 0.9% saline (voluven) and a balanced solution (plasma volume Redibag) on blood volume, renal blood flow velocity, and renal cortical tissue perfusion in healthy volunteers. Ann Surg. 2014; 259: 881– 887. doi: 10.1097/SLA.0000000000000324 24253140 · DOI
  25. [29]Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest. 1983; 71: 726– 735. doi: 10.1172/JCI110820 6826732 PMC436923 · DOI
  26. [30]Lankadeva YR, Evans RG, Kosaka J, Booth LC, Iguchi N, Bellomo R, May CN. Alterations in regional kidney oxygenation during expansion of extracellular fluid volume in conscious healthy sheep. Am J Physiol Regul Integr Comp Physiol. 2018; 315: R1242– R1250. doi: 10.1152/ajpregu.00247.2018 30332304 · DOI
  27. [31]Assersen KB, Høilund‐Carlsen PF, Olsen MH, Greve SV, Gam‐Hadberg JC, Braad P‐E, Damkjaer M, Bie P. The exaggerated natriuresis of essential hypertension occurs independently of changes in renal medullary blood flow. Acta Physiol (Oxf). 2019; 226: e13266. doi: 10.1111/apha.13266 30770642 · DOI
  28. [32]Bradley CR, Bragg DD, Cox EF, El‐Sharkawy AM, Buchanan CE, Chowdhury AH, Macdonald IA, Francis ST, Lobo DN. A randomized, controlled, double‐blind crossover study on the effects of isoeffective and isovolumetric intravenous crystalloid and gelatin on blood volume, and renal and cardiac hemodynamics. Clin Nutr. 2020; 39: 2070– 2079. doi: 10.1016/j.clnu.2019.09.011 31668721 PMC7359406 · DOI
  29. [33]Zhang Z, Huang JM, Turner MR, Rhinehart KL, Pallone TL. Role of chloride in constriction of descending vasa recta by angiotensin II. Am J Physiol Regul Integr Comp Physiol. 2001; 280: R1878– R1886. doi: 10.1152/ajpregu.2001.280.6.R1878 11353695 · DOI
  30. [34]Jensen BL, Ellekvist P, Skøtt O. Chloride is essential for contraction of afferent arterioles after agonists and potassium. Am J Physiol. 1997; 272: F389– F396. doi: 10.1152/ajprenal.1997.272.3.F389 9087683 · DOI
  31. [35]Schnermann J, Ploth DW, Hermle M. Activation of tubulo‐glomerular feedback by chloride transport. Pflugers Arch. 1976; 362: 229– 240. doi: 10.1007/BF00581175 944430 · DOI
  32. [36]Mattson DL. Importance of the renal medullary circulation in the control of sodium excretion and blood pressure. Am J Physiol Regul Integr Comp Physiol. 2003; 284: R13– R27. doi: 10.1152/ajpregu.00321.2002 12482743 · DOI
  33. [37]Mattson DL, Cowley AW. Kinin actions on renal papillary blood flow and sodium excretion. Hypertension. 1993; 21: 961– 965. doi: 10.1161/01.HYP.21.6.961 8505107 · DOI
  34. [39]Drucker DJ. The biology of incretin hormones. Cell Metab. 2006; 3: 153– 165. doi: 10.1016/j.cmet.2006.01.004 16517403 · DOI · Paper page
  35. [40]Lezoualc'h F, Fazal L, Laudette M, Conte C. Cyclic AMP sensor EPAC proteins and their role in cardiovascular function and disease. Circ Res. 2016; 118: 881– 897. doi: 10.1161/CIRCRESAHA.115.306529 26941424 · DOI
  36. [41]van der Bel R, Coolen BF, Nederveen AJ, Potters WV, Verberne HJ, Vogt L, Stroes ESG, Krediet CTP. Magnetic resonance imaging‐derived renal oxygenation and perfusion during continuous, steady‐state angiotensin‐II infusion in healthy humans. J Am Heart Assoc. 2016; 5: e003185. doi: 10.1161/JAHA.115.003185 27021686 PMC4943284 · DOI
  37. [42]Dwan K, Li T, Altman DG, Elbourne D. CONSORT 2010 statement: extension to randomised crossover trials. BMJ. 2019; 366: l4378. doi: 10.1136/bmj.l4378 31366597 PMC6667942 · DOI · Paper page

Authors
Haddock, B., Kristensen, K. B., Tayyab, M., Larsson, H. B. W., Lindberg, U., Vestergaard, M., Francis, S., Jensen, B. L., Andersen, U. B., & Asmar, A.
Affiliations
  • Copenhagen University Hospital (DK)
  • University of Nottingham (GB)
  • University of Southern Denmark (DK)
  • University of Copenhagen (DK)
Corresponding author
Asmar, Ali
ORCID
Venue
Journal of the American Heart Association
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2023-02-07
Volume
12
Issue
3
Pages
e027712-e027712
ISSN
2047-9980 (ISSN-L)
DOI
10.1161/jaha.122.027712
PMC
PMC9973647
OpenAlex
W4319062772
Cited by
23
References
44
Citations by year
2026: 5 · 2025: 10 · 2024: 5 · 2023: 3
FWCI
4.72
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Journal of the American Heart Association (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
  • Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Repository@Nottingham (University of Nottingham) (submittedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, cc-by-nc-nd)
Funders
  • Novo Nordisk
  • Medical Research Council (MR/R02264X/1)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
Keywords
glucagon-like peptide-1, GLP-1 receptor agonists, renal cortical perfusion, renal oxygenation, sodium chloride loading, angiotensin II, renal blood flow, vasa recta
MeSH terms
Adult, Angiotensin II, Humans, Kidney, Kidney Medulla, Male, Perfusion, Renal Circulation, Sodium Chloride, Cross-Over Studies, Glucagon-Like Peptide 1, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review