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  • Review Article
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Calcium signalling and transport in the kidney

Nature Reviews Nephrology (2024)Cite this article

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Abstract

The kidney plays a pivotal role in regulating calcium levels within the body. Approximately 98% of the filtered calcium is reabsorbed in the nephron, and this process is tightly controlled to maintain calcium homeostasis, which is required to facilitate optimal bone mineralization, preserve serum calcium levels within a narrow range, and support intracellular signalling mechanisms. The maintenance of these functions is attributed to a delicate balance achieved by various calcium channels, transporters, and calcium-binding proteins in renal cells. Perturbation of this balance due to deficiency or dysfunction of calcium channels and calcium-binding proteins can lead to severe complications. For example, polycystic kidney disease is linked to aberrant calcium transport and signalling. Furthermore, dysregulation of calcium levels can promote the formation of kidney stones. This Review provides an updated description of the key aspects of calcium handling in the kidney, focusing on the function of various calcium channels and the physiological stimuli that control these channels or are communicated through them. A discussion of the role of calcium as an intracellular second messenger and the pathophysiology of renal calcium dysregulation, as well as a summary of gaps in knowledge and future prospects, are also included.

Key points

  • The kidney has an essential role in the maintenance of serum calcium levels owing to its careful regulation of reabsorption along the nephron, which contributes to whole-body calcium balance.

  • Physiologically relevant mechanisms that control calcium channels in the kidney include endocrine and paracrine signals and physical factors such as fluid flow.

  • Tight control of calcium influx and intracellular calcium levels maintains intracellular calcium concentrations within the physiological range, despite acute and chronic variation in calcium intake.

  • Failure to reabsorb calcium from renal tubules results in hypercalciuria and an increased risk of kidney stones.

  • Aberrant calcium signalling in particular renal cell types is a hallmark of renal diseases such as polycystic kidney disease and focal segmental glomerulosclerosis.

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Fig. 1: Calcium metabolism and flux between body compartments.
Fig. 2: Reabsorption of the filtered calcium load in the nephron.
Fig. 3: Important determinants of paracellular and transcellular calcium reabsorption along the nephron.
Fig. 4: Renal pathologies associated with altered calcium channel activity.

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Acknowledgements

The authors apologize to the investigators of renal calcium transport whose relevant publications were inadvertently not directly discussed. The authors’ research was supported by National Institutes of Health grants R35 HL135749, R01 DK135644, R01 DK129227 (to A.S.), R01 HL148114 (to D.V.I.), RC2 DK120534-01 (to M.J.C.), Department of Defense PR191158 (to M.J.C.), American Heart Association Transformational Project Award TPA35490039 (to A.S.), the Department of Veteran Affairs grant I01 BX004024 (to A.S.) and by The Women and Children’s’ Health Research Institute (R.T.A.), The Canadian Institutes of Health Research (R.T.A.), and The Natural Sciences and Engineering Research Council of Canada (R.T.A.).

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Authors and Affiliations

  1. Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA

    Alexander Staruschenko

  2. Hypertension and Kidney Research Center, University of South Florida, Tampa, FL, USA

    Alexander Staruschenko

  3. James A. Haley Veterans Hospital, Tampa, FL, USA

    Alexander Staruschenko

  4. Department of Paediatrics, University of Alberta, Edmonton, AB, Canada

    R. Todd Alexander

  5. Women’s and Children’s Health Institute, Edmonton, AB, Canada

    R. Todd Alexander

  6. Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA

    Michael J. Caplan

  7. Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, USA

    Daria V. Ilatovskaya

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Staruschenko, A., Alexander, R.T., Caplan, M.J. et al. Calcium signalling and transport in the kidney. Nat Rev Nephrol (2024). https://doi.org/10.1038/s41581-024-00835-z

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