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The (pro)renin receptor in health and disease

Nature Reviews Nephrology volume 15, pages 693–712 (2019)Cite this article

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Abstract

The (pro)renin receptor ((P)RR) was first identified as a single-transmembrane receptor in human kidneys and initially attracted attention owing to its potential role as a regulator of the tissue renin–angiotensin system (RAS). Subsequent studies found that the (P)RR is widely distributed in organs throughout the body, including the kidneys, heart, brain, eyes, placenta and the immune system, and has multifaceted functions in vivo. The (P)RR has roles in various physiological processes, such as the cell cycle, autophagy, acid–base balance, energy metabolism, embryonic development, T cell homeostasis, water balance, blood pressure regulation, cardiac remodelling and maintenance of podocyte structure. These roles of the (P)RR are mediated by its effects on important biological systems and pathways including the tissue RAS, vacuolar H+-ATPase, Wnt, partitioning defective homologue (Par) and tyrosine phosphorylation. In addition, the (P)RR has been reported to contribute to the pathogenesis of diseases such as fibrosis, hypertension, pre-eclampsia, diabetic microangiopathy, acute kidney injury, cardiovascular disease, cancer and obesity. Current evidence suggests that the (P)RR has key roles in the normal development and maintenance of vital organs and that dysfunction of the (P)RR is associated with diseases that are characterized by a disruption of the homeostasis of physiological functions.

Key points

  • The (pro)renin receptor ((P)RR) is a ubiquitously expressed, single-transmembrane receptor protein with a molecular mass of 39 kDa; the carboxy-terminal domain of the (P)RR binds to the vacuolar H+-ATPase (V-ATPase).

  • Ligands that bind to the (P)RR amino-terminal domain include renin, prorenin, partitioning defective homologue 3 (Par3), PDH E1 β-subunit (PDHB), LDL receptor-related protein 6 (LRP6), phosphatase of regenerating liver 1 (PRL1), actin binding LIM protein 2 (abLIM2), capping actin protein of muscle Z-line subunit-α2 (CAPZA2) and vertebrate homologue of flamingo (CELSR).

  • At least three enzymes — furin, ADAM19 and site 1 protease (S1P) — cleave off the amino-terminal domain of the (P)RR to produce soluble (P)RR.

  • In addition to angiotensin II generation, the (P)RR is involved in angiotensin-II-independent formation and function of the V-ATPase, Wnt signalling, the Par3 system, regulation of the tissue renin–angiotensin system (RAS) and tyrosine-phosphorylation-dependent signalling pathways.

  • Physiological functions of the (P)RR include roles in the cell cycle, autophagy, acid–base balance, energy metabolism, embryonic development, T cell homeostasis, water balance, blood pressure regulation, cardiac remodelling and maintenance of podocyte structure.

  • The (P)RR may participate in the pathogenesis of fibrosis, hypertension, pre-eclampsia, impaired glucose tolerance, diabetic microangiopathy, acute kidney injury, chronic kidney disease, cardiovascular disease, cancer, obesity and various other diseases.

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Fig. 1: Multiple functions of the (P)RR.
Fig. 2: The roles of the (P)RR and s(P)RR in renal physiology and disease.
Fig. 3: The role of the (P)RR in blood pressure regulation and the development of hypertension.
Fig. 4: Potential role of the (P)RR in hypertensive disorders of pregnancy.

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Acknowledgements

The authors’ work was supported in part by a Japan Society for the Promotion of Science (JSPS) KAKENHI grant (16H05316) to A.I. The authors thank C. Miki at Tokyo Women’s Medical University Department of Endocrinology and Hypertension for her clerical assistance.

Reviewer information

Nature Reviews Nephrology thanks S. Ito, T. Nakagawa, J. Peters and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Department of Endocrinology and Hypertension, Tokyo Women’s Medical University, Shinjuku, Tokyo, Japan

    Atsuhiro Ichihara & Midori Sasaki Yatabe

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  1. Atsuhiro Ichihara
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A.I. researched the data for the article. A.I. and M.S.Y. wrote the text and reviewed or edited the manuscript before submission.

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Correspondence to Atsuhiro Ichihara.

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Supplementary information

Glossary

Adherens junctions

Epithelial cell–cell junctions that are composed of cadherins and catenins; the cytoplasmic side of the junction complex is linked to the actin cytoskeleton.

Local tissue RAS

Angiotensin II generation and action in local tissues that operates separately from the circulating renin–angiotensin system (RAS).

Handle region

Prorenin prosegment that binds to the (pro)renin receptor ((P)RR). This binding induces a conformational change in prorenin that exposes its catalytic cleft and leads to its non-proteolytic activation.

A-type K+ channels

Transmembrane, rapidly inactivating voltage-gated potassium channels.

Vasopressin neurons

Hypothalamic neurons that produce vasopressin (also known as antidiuretic hormone (ADH) or arginine vasopressin (AVP)). These neurons release vasopressin from the posterior lobe of the pituitary gland.

Z-disc

A structure that defines the boundaries of a sarcomere, which is the contractile unit of the muscle cell. Thin filaments of actin attach to the Z-disc in muscle cells.

Dyad

A structure in cardiomyocytes that couples transverse tubules to the sarcoplasmic reticulum.

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Ichihara, A., Yatabe, M.S. The (pro)renin receptor in health and disease. Nat Rev Nephrol 15, 693–712 (2019). https://doi.org/10.1038/s41581-019-0160-5

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