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The therapeutic potential of apelin in kidney disease

Nature Reviews Nephrology volume 17, pages 840–853 (2021)Cite this article

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Abstract

Chronic kidney disease (CKD) is a leading cause of global morbidity and mortality and is independently associated with cardiovascular disease. The mainstay of treatment for CKD is blockade of the renin–angiotensin–aldosterone system (RAAS), which reduces blood pressure and proteinuria and slows kidney function decline. Despite this treatment, many patients progress to kidney failure, which requires dialysis or kidney transplantation, and/or die as a result of cardiovascular disease. The apelin system is an endogenous physiological regulator that is emerging as a potential therapeutic target for many diseases. This system comprises the apelin receptor and its two families of endogenous ligands, apelin and elabela/toddler. Preclinical and clinical studies show that apelin receptor ligands are endothelium-dependent vasodilators and potent inotropes, and the apelin system has a reciprocal relationship with the RAAS. In preclinical studies, apelin regulates glomerular haemodynamics and acts on the tubule to promote aquaresis. In addition, apelin is protective in several kidney injury models. Although the apelin system has not yet been studied in patients with CKD, the available data suggest that apelin is a promising potential therapeutic target for kidney disease.

Key points

  • Chronic kidney disease (CKD) is common worldwide and is associated with high cardiovascular morbidity and mortality; however, treatment options are limited.

  • The apelin system is a broad regulator of physiology that opposes the renin–angiotensin–aldosterone system (RAAS) and has beneficial cardiovascular effects in health and disease.

  • Increasing evidence indicates that apelin has favourable effects on renal physiology, including roles in the regulation of fluid balance and glomerular haemodynamics.

  • Preclinical models demonstrate direct anti-inflammatory and anti-fibrotic actions of the apelin system in models of kidney injury; targeting the apelin receptor in combination with RAAS blockers might offer synergistic benefits.

  • The apelin system is an attractive potential therapeutic target for CKD, offering direct renal protection in addition to targeting the associated cardiovascular complications.

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Fig. 1: The peptide sequences of apelin and ELA isoforms.
Fig. 2: Apelin receptor activation leads to a broad range of physiological actions that are mediated by several signalling pathways.
Fig. 3: Physiological actions of the apelin system in different organs and tissues.
Fig. 4: The actions of apelin in the nephron.

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Acknowledgements

F.A.C. is supported by a Kidney Research UK Training Fellowship (TF_006_20171124). D.N., J.J.M. and A.P.D. are supported in whole or part by the Wellcome Trust (WT203814/Z/16/A for D.N.; WT107715/Z/15/Z for A.P.D. and J.J.M.). D.E.N. is supported by the British Heart Foundation (FS/06/064, FS/09/019, CH09/002, RG/16/10/32375, RE/18/5/34216) and Wellcome Trust (WT103782AIA). N.D. is supported by a Senior Clinical Research Fellowship from the Chief Scientist Office (SCAF/19/02).

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Authors and Affiliations

  1. BHF/University Centre for Cardiovascular Science, The Queen’s Medical Research Institute, Edinburgh, UK

    Fiona A. Chapman, David E. Newby & Neeraj Dhaun

  2. Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK

    Fiona A. Chapman & Neeraj Dhaun

  3. Division of Experimental Medicine and Immunotherapeutics, Addenbrooke’s Centre for Clinical Investigation, University of Cambridge, Cambridge, UK

    Duuamene Nyimanu, Janet J. Maguire & Anthony P. Davenport

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Glossary

‘Message–address’ concept of peptide binding

The concept that agonists contain two distinct parts: one determines receptor efficacy and activation (the ‘message’); the other influences receptor selectivity (the ‘address’).

Inotrope

A substance that alters the force of contraction of a muscle. This term is normally used to refer to effects on the myocardium and, unless otherwise specified, implies increased contractility.

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Chapman, F.A., Nyimanu, D., Maguire, J.J. et al. The therapeutic potential of apelin in kidney disease. Nat Rev Nephrol 17, 840–853 (2021). https://doi.org/10.1038/s41581-021-00461-z

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