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Nitric oxide signalling in kidney regulation and cardiometabolic health

Nature Reviews Nephrology volume 17, pages 575–590 (2021)Cite this article

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Abstract

The prevalence of cardiovascular and metabolic disease coupled with kidney dysfunction is increasing worldwide. This triad of disorders is associated with considerable morbidity and mortality as well as a substantial economic burden. Further understanding of the underlying pathophysiological mechanisms is important to develop novel preventive or therapeutic approaches. Among the proposed mechanisms, compromised nitric oxide (NO) bioactivity associated with oxidative stress is considered to be important. NO is a short-lived diatomic signalling molecule that exerts numerous effects on the kidneys, heart and vasculature as well as on peripheral metabolically active organs. The enzymatic l-arginine-dependent NO synthase (NOS) pathway is classically viewed as the main source of endogenous NO formation. However, the function of the NOS system is often compromised in various pathologies including kidney, cardiovascular and metabolic diseases. An alternative pathway, the nitrate–nitrite–NO pathway, enables endogenous or dietary-derived inorganic nitrate and nitrite to be recycled via serial reduction to form bioactive nitrogen species, including NO, independent of the NOS system. Signalling via these nitrogen species is linked with cGMP-dependent and independent mechanisms. Novel approaches to restoring NO homeostasis during NOS deficiency and oxidative stress have potential therapeutic applications in kidney, cardiovascular and metabolic disorders.

Key points

  • Nitric oxide and other bioactive nitrogen species have pivotal roles in multiple physiological functions, including modulation of the kidney, cardiovascular and metabolic systems; in the kidney, nitric oxide has a crucial role in autoregulation and modulation of tubular transport.

  • Nitric oxide is classically derived from l-arginine-dependent nitric oxide synthases, but can also be formed via serial reduction of inorganic nitrate and nitrite, that is, the nitrate–nitrite–nitric oxide pathway.

  • The nitrate–nitrite–nitric oxide pathway can be boosted via the diet and is of particular importance in conditions where the activity of the nitric oxide synthase system is reduced, such as hypoxia, ischaemia or low pH.

  • Signalling via bioactive nitrogen species is linked with both cGMP-dependent and independent mechanisms.

  • Reduced nitric oxide bioactivity has been associated with ageing and kidney, cardiovascular and metabolic disorders, which are often coupled with oxidative stress.

  • Novel pharmacological and nutritional strategies that increase nitric oxide bioactivity and reduce oxidative stress could be potential therapies for preventing and treating kidney disease and associated cardiometabolic complications.

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Fig. 1: The NOS pathway and potential effects of NO on cardiovascular, renal and metabolic functions.
Fig. 2: The generation of bioactive NO in mammals.
Fig. 3: cGMP-independent signalling via bioactive nitrogen species.
Fig. 4: Effects of NO on sodium transporters in the nephron.
Fig. 5: Strategies to restore NO bioactivity.

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Acknowledgements

M.C. sincerely thanks all co‑authors of the original articles from their groups, which are highlighted in this Review. A special thanks to E. Weitzberg and J. O. Lundberg (Karolinska Institutet) for valuable comments on the manuscript, and to S. McCann Haworth (Karolinska Institutet) for language editing before submission. M.C. receives research support from the Swedish Research Council (2016-01381, 2020-01645), the Swedish Heart and Lung Foundation (20170124, 20180568), NovoNordisk (2019#0055026) and by EFSD/Lilly European Diabetes Research Programme (2018#97012), Stockholm County Council Research Funding (ALF, 20190314), as well as Research Funds (2-560/2015) and KID funding (2-3707/2013 & 2-1930/2016) from the Karolinska Institutet, Stockholm, Sweden.

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    Mattias Carlström

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Glossary

Nitrosylation

The formation of a nitrosyl species (X-NO, where X represents a metal centre or radical species) via a direct reaction with NO.

Nitration

The addition of a nitronium ion (NO2+) to a nucleophilic group, leading to the generation of an X-NO2 species (formation of a nitro group).

Transnitrosation

The transfer of NO+ from one nucleophilic centre to another.

Transnitrosylation

The transfer of NO from one molecule to another.

Myogenic response

The intrinsic capacity of small resistance arteries and arterioles to react (contract or dilate) in response to variations in blood pressure to keep the blood flow constant.

Tubuloglomerular feedback

(TGF). A unique feedback system in which macula densa cells sense tubular NaCl load and communicate via purinergic signalling with the afferent arteriole, which adjusts its tone to regulate the glomerular filtration rate.

Vascular conductance

The ease with which blood flows through a circulation (or vascular bed) at a given pressure difference (the reciprocal of resistance).

Vascular admittance

A relative autoregulatory index that is similar to steady-state conductance (the reciprocal of resistance).

Nitrosation

The addition of a nitrosonium ion (NO+) to a nucleophilic centre (e.g. a thiol or amine) either directly or by transfer from an NO+ donor (e.g. N2O3 or FeIINO+).

Dietary Approaches to Stop Hypertension (DASH) diet

A diet rich in fruits, vegetables and low-fat dairy products, that was developed by the nutrition committee of the American Heart Association and has been shown to reduce blood pressure.

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Carlström, M. Nitric oxide signalling in kidney regulation and cardiometabolic health. Nat Rev Nephrol 17, 575–590 (2021). https://doi.org/10.1038/s41581-021-00429-z

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