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Role of perivascular cells in kidney homeostasis, inflammation, repair and fibrosis

Nature Reviews Nephrology volume 19, pages 721–732 (2023)Cite this article

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Abstract

Perivascular niches in the kidney comprise heterogeneous cell populations, including pericytes and fibroblasts, with distinct functions. These perivascular cells have crucial roles in preserving kidney homeostasis as they maintain microvascular networks by stabilizing the vasculature and regulating capillary constriction. A subset of kidney perivascular cells can also produce and secrete erythropoietin; this ability can be enhanced with hypoxia-inducible factor-prolyl hydroxylase inhibitors, which are used to treat anaemia in chronic kidney disease. In the pathophysiological state, kidney perivascular cells contribute to the progression of kidney fibrosis, partly via transdifferentiation into myofibroblasts. Moreover, perivascular cells are now recognized as major innate immune sentinels in the kidney that produce pro-inflammatory cytokines and chemokines following injury. These mediators promote immune cell infiltration, leading to persistent inflammation and progression of kidney fibrosis. The crosstalk between perivascular cells and tubular epithelial, immune and endothelial cells is therefore a key process in physiological and pathophysiological states. Here, we examine the multiple roles of kidney perivascular cells in health and disease, focusing on the latest advances in this field of research.

Key points

  • Perivascular niches in the kidney comprise heterogeneous cell populations, including pericytes and fibroblasts, with distinct functions. These perivascular cells have crucial roles in maintaining homeostasis in the kidney.

  • Pericytes maintain microvascular networks by stabilizing the vasculature and modulating the constriction of capillaries. In pathological states, such as ischaemia–reperfusion, pericytes contribute to the ‘no-reflow’ phenomenon.

  • A subset of kidney perivascular cells can produce and secrete erythropoietin; hypoxia-inducible factor-prolyl hydroxylase inhibitors can boost this secretion and are used for the treatment of anaemia in chronic kidney disease.

  • Perivascular cells or platelet-derived growth factor receptor-β+ (PDGFRβ+) pericytes synthesize and secrete various intracellular complement proteins and contribute to expression of collagen and extracellular matrix observed during the development of kidney fibrosis.

  • In pathophysiological states, kidney perivascular cells contribute to the progression of kidney fibrosis, partly by transdifferentiating into myofibroblasts.

  • Perivascular cells are major innate immune sentinels in the kidney and produce pro-inflammatory cytokines and chemokines after injury; these mediators promote immune cell infiltration, leading to persistent inflammation and progression of kidney fibrosis.

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Fig. 1: Pericytes, macrophages and sympathetic nerve terminals in the kidney microenvironment.
Fig. 2: Pericytes regulate microvascular blood flow.
Fig. 3: Oxygen-sensing system via the HIF-PH–HIF axis.
Fig. 4: Origin of myofibroblasts.
Fig. 5: Crosstalk between kidney perivascular cells or myofibroblasts, and adjacent cells in the pathophysiological state.
Fig. 6: Complement in the kidney tissue microenvironment contributes to tubulointerstitial fibrosis.

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Acknowledgements

The authors thank D. Rosin for careful reading of the manuscript before submission. Work in the laboratory of S.T. is funded by JSPS KAKENHI (JP21K20894, JP22K16232), AMED (JP22gm6510016), the Ichiro Kanehara Foundation, MSD Life Science Foundation, the Uehara Memorial Foundation, Life Science Foundation of Japan, the Salt Science Research Foundation (2327), Research Fund of Mitsukoshi Health and Welfare Foundation 2022, and Kobayashi Foundation. Work in the laboratory of D.P. is funded by National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01 DK 12262401A1). Work in the laboratory of M.D.O. is supported by the NIDDK (R01DK085259 and R01DK123248).

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  1. Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan

    Shinji Tanaka

  2. Division of Nephrology and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, VA, USA

    Didier Portilla & Mark D. Okusa

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Tanaka, S., Portilla, D. & Okusa, M.D. Role of perivascular cells in kidney homeostasis, inflammation, repair and fibrosis. Nat Rev Nephrol 19, 721–732 (2023). https://doi.org/10.1038/s41581-023-00752-7

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