Abstract
Chronic kidney disease (CKD), defined as persistent (>3 months) kidney functional loss, has a growing prevalence (>10% worldwide population) and limited treatment options. Fibrosis driven by the aberrant accumulation of extracellular matrix is the final common pathway of nearly all types of chronic repetitive injury in the kidney and is considered a hallmark of CKD. Myofibroblasts are key extracellular matrix-producing cells that are activated by crosstalk between damaged tubules and immune cells. Emerging evidence indicates that metabolic alterations are crucial contributors to the pathogenesis of kidney fibrosis by affecting cellular bioenergetics and metabolite signalling. Immune cell functions are intricately connected to their metabolic characteristics, and kidney cells seem to undergo cell-type-specific metabolic shifts in response to damage, all of which can determine injury and repair responses in CKD. A detailed understanding of the heterogeneity in metabolic reprogramming of different kidney cellular subsets is essential to elucidating communication processes between cell types and to enabling the development of metabolism-based innovative therapeutic strategies against CKD.
Key points
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The kidney has distinctive anatomical and physiological characteristics, and kidney cell types have specialized metabolic traits tailored to their specific functions and location.
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In general, all kidney cells — including epithelial, endothelial, stromal and immune cells — can have an impact on fibrosis, and their roles are determined by spatiotemporal metabolic reprogramming that coordinates their effector functions and interactions.
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Identification of cell-type-specific metabolic shifts could enable the recognition of novel cell subpopulations with distinctive roles in adaptive or fibrotic kidney regeneration.
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Targeting metabolic routes and energy-sensing molecules to promote an immune anti-inflammatory or quiescent state might avoid chronic inflammation and subsequent development of kidney fibrosis.
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Acknowledgements
This work was supported by grants from the German Research Foundation (DFG: SFBTRR219) CRU344 4288578857858 and CRU5011 445703531, a grant from the Else Kroener Fresenius Foundation, the Dutch Kidney Foundation TASKFORCE EP1805 and Kolff Grant #113351, the Leducq Foundation, the BMBF eMed Consortia Fibromap and the BMBF Consortia CureFib to R.K. V.M. was supported by a FEBS Long-Term Fellowship. I.W.S. is funded by a Benjamin Hochberg Fellowship from the DFG.
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Miguel, V., Shaw, I.W. & Kramann, R. Metabolism at the crossroads of inflammation and fibrosis in chronic kidney disease. Nat Rev Nephrol (2024). https://doi.org/10.1038/s41581-024-00889-z
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DOI: https://doi.org/10.1038/s41581-024-00889-z
