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Renin cells in homeostasis, regeneration and immune defence mechanisms

Nature Reviews Nephrology volume 14, pages 231–245 (2018)Cite this article

Subjects

Key Points

  • Renin-expressing cells are evolutionarily conserved and have retained features to contribute to the defence against threats to survival such as bleeding, dehydration, hypotension and/or hypoxia

  • In the embryo, renin-expressing cells populate diverse tissues where they might have a role in tissue morphogenesis and growth; in the developing kidney, they are progenitors for arteriolar and mesangial cells and are crucial for arteriolar branching morphogenesis

  • In adults, cells derived from progenitors that previously expressed renin retain their developmental memory and can regenerate injured glomeruli or re-express renin to achieve blood pressure and fluid–electrolyte homeostasis

  • Renin-expressing cells are linked to other fundamental homeostatic systems, such as the haematopoietic and circulating leukocyte renin–angiotensin systems, through which they might contribute to bone marrow development and the local control of inflammation or infections

  • Renin-expressing cells intersect with erythropoietin-producing cells and are therefore at the crossroads of two key life-sustaining systems involved in the control of fluid volume, perfusion pressure and oxygen delivery to tissues

Abstract

An accumulating body of evidence suggests that renin-expressing cells have developed throughout evolution as a mechanism to preserve blood pressure and fluid volume homeostasis as well as to counteract a number of homeostatic and immunological threats. In the developing embryo, renin precursor cells emerge in multiple tissues, where they differentiate into a variety of cell types. The function of those precursors and their progeny is beginning to be unravelled. In the developing kidney, renin-expressing cells control the morphogenesis and branching of the renal arterial tree. The cells do not seem to fully differentiate but instead retain a degree of developmental plasticity or molecular memory, which enables them to regenerate injured glomeruli or to alter their phenotype to control blood pressure and fluid–electrolyte homeostasis. In haematopoietic tissues, renin-expressing cells might regulate bone marrow differentiation and participate in a circulating leukocyte renin–angiotensin system, which acts as a defence mechanism against infections or tissue injury. Furthermore, renin-expressing cells have an intricate lineage and functional relationship with erythropoietin-producing cells and are therefore central to two endocrine systems — the renin–angiotensin and erythropoietin systems — that sustain life by controlling fluid volume and composition, perfusion pressure and oxygen delivery to tissues. However, loss of the homeostatic control of these systems following dysregulation of renin-expressing cells can be detrimental, with serious pathological events.

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Figure 1: Distribution and origin of renin-expressing cells in renal and extrarenal sites.
Figure 2: Progenitor compartments and nephrovascular development.
Figure 3: Localization of renin-expressing cells throughout branching morphogenesis of the renal arterial tree.
Figure 4: The Notch/RBP-J signalling pathway controls the fate of stromal and renin cell precursors.
Figure 5: Major mechanisms controlling renin synthesis and release.
Figure 6: Mechanisms to increase the number of renin-expressing cells.
Figure 7: Interaction between renin-expressing cells and the erythropoietin–oxygen delivery system.
Figure 8: Vascular alterations upon ablation of the renin–angiotensin system.

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Acknowledgements

The authors thank H. Watanabe, B. Belyea and E. Brown (University of Virginia, Charlottesville, USA) for their comments on the manuscript and figures. Studies were funded by the US National Institutes of Health, Grants DK-096373 and HL-096735 to R.A.G. and DK-091330 and DK-096373 to M.L.S.S.-L.

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  1. Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, 22908, VA, USA

    R. Ariel Gomez & Maria Luisa S. Sequeira-Lopez

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  1. R. Ariel Gomez
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Both authors contributed equally to researching data for the article, discussion of the content, writing the article and revising and/or editing the manuscript before submission.

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Correspondence to R. Ariel Gomez.

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PowerPoint slides

Glossary

Juxtaglomerular cells

A specialized group of renin-producing, myo-epithelioid, granulated cells located at the tip of the afferent arterioles at the entrance to the glomeruli.

Juxtaglomerular apparatus

The functional sensory and responding unit of the renin–angiotensin system; it is composed of the afferent and efferent arterioles, the macula densa and the extraglomerular mesangium.

Plasticity

The ability of cells to switch phenotypes.

Metanephros

The definitive kidney of adult mammals.

Fetal zone

A large, eosinophilic steroidogenic group of cells of the fetal adrenal gland, which is believed to involute after birth.

Mural cells

Cells located within the wall(s) of the renal arterioles, including smooth muscle cells and renin-expressing cells such as juxtaglomerular cells. In larger arteries, adventitial cells such as fibroblasts and perivascular pericytes are sometimes considered mural cells. Although part of the arterial wall, endothelial cells are not usually considered mural cells.

Stromal compartment

One of the three main compartments of the developing kidney; it contains FOXD1+ progenitors of vascular smooth muscle cells, renin-expressing cells, mesangial cells and pericytes as well as SCL+ progenitors of endothelial cells of arteries and arterioles, glomeruli and interstitial capillaries.

Vasculogenesis

De novo, local differentiation and assembly of blood vessels from resident progenitor cells that are usually derived from multiple clones.

Angiogenesis

The formation of new blood vessels, usually by sprouting of new branches from pre-existing vessels. This process usually involves the proliferation and/or elongation of cells from single clones. In the case of arterioles, it is followed by the recruitment of perivascular smooth muscle cells.

Fractal

A shape or structure made of smaller parts or units that repeat themselves and resemble the whole.

Developmental memory

The ability of cells to expressly re-acquire a phenotype previously expressed during development.

Metaplastic transformation

Pathological transformation of one cell type into another not related by lineage.

Hyperplasia

Increase in cell number, usually due to increased cell proliferation.

Neogenesis

De novo expression of a gene (for example, renin) in a cell that has not previously expressed the gene.

Direct transdifferentiation

Transformation of one cell into another without reprogramming into induced pluripotent stem cells.

Erythrocytosis

Increase in red cell mass.

Leukaemic blast cells

Immature forms of white blood cells that fail to differentiate normally and proliferate in an uncontrolled manner, leading to tissue infiltration and, if untreated, death.

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Gomez, R., Sequeira-Lopez, M. Renin cells in homeostasis, regeneration and immune defence mechanisms. Nat Rev Nephrol 14, 231–245 (2018). https://doi.org/10.1038/nrneph.2017.186

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