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Sirtuins in kidney health and disease

Nature Reviews Nephrology volume 20, pages 313–329 (2024)Cite this article

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Abstract

Sirtuins (SIRTs) are putative regulators of lifespan in model organisms. Since the initial discovery that SIRTs could promote longevity in nematodes and flies, the identification of additional properties of these proteins has led to understanding of their roles as exquisite sensors that link metabolic activity to oxidative states. SIRTs have major roles in biological processes that are important in kidney development and physiological functions, including mitochondrial metabolism, oxidative stress, autophagy, DNA repair and inflammation. Furthermore, altered SIRT activity has been implicated in the pathophysiology and progression of acute and chronic kidney diseases, including acute kidney injury, diabetic kidney disease, chronic kidney disease, polycystic kidney disease, autoimmune diseases and renal ageing. The renoprotective roles of SIRTs in these diseases make them attractive therapeutic targets. A number of SIRT-activating compounds have shown beneficial effects in kidney disease models; however, further research is needed to identify novel SIRT-targeting strategies with the potential to treat and/or prevent the progression of kidney diseases and increase the average human healthspan.

Key points

  • Sirtuins (SIRTs) were initially of great scientific interest owing to their putative roles in modulating lifespan in experimental models; however, they are now generally understood to be drivers of healthy ageing.

  • SIRTs regulate key processes in cellular homeostasis, including metabolism, mitochondrial functions, oxidative stress, DNA repair, apoptosis, senescence and inflammation.

  • SIRTs have essential roles in kidney development and physiology owing to their broad cytoprotective effects in highly specialized and differentiated renal cell types, including podocytes and tubular cells.

  • SIRT alterations have been identified as drivers of various kidney diseases in humans and experimental models, including acute kidney injury, chronic kidney disease and diabetic kidney disease.

  • The identification of sirtuin-activating compounds is a major goal in the field; some sirtuin-activating compounds have been shown to boost SIRT activity and confer renoprotection in experimental models but few have reached clinical trials.

  • Novel SIRT-targeting compounds with improved potency and bioavailability are needed to realize the potential of these interventions to treat and prevent kidney diseases and increase the human healthspan.

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Fig. 1: SIRT localization, structure and enzymatic activity.
Fig. 2: NAD+ functions and biosynthetic pathways.
Fig. 3: Overview of the main biological processes regulated by sirtuins.
Fig. 4: Sirtuins in kidney health and disease.

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    Luca Perico, Giuseppe Remuzzi & Ariela Benigni

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Perico, L., Remuzzi, G. & Benigni, A. Sirtuins in kidney health and disease. Nat Rev Nephrol 20, 313–329 (2024). https://doi.org/10.1038/s41581-024-00806-4

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