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  • Review Article
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The importance of the intrarenal renin–angiotensin system

Nature Clinical Practice Nephrology volume 5, pages 89–100 (2009)Cite this article

Abstract

Evidence suggests that virtually every organ system in the human body possesses a local renin–angiotensin system (RAS). These local systems seem to be independently regulated and compartmentalized from the plasma circulation, perhaps with the exception of the vascular endothelial system, which is responsible for maintaining physiological plasma levels of RAS components. Among these local RASs, the kidney RAS—the focus of this Review—seems to be of critical importance for the regulation of blood pressure and salt balance. Indeed, overactivation of the intrarenal RAS in certain disease states constitutes a pathogenic mechanism that leads to tissue injury, proliferation, fibrosis and ultimately, end-organ damage. Intrarenal levels of angiotensin peptides are considerably higher than those in plasma or any other organ tissue. Moreover, the kidney has a unique capacity to degrade angiotensin peptides, perhaps to maintain its intrinsic homeostasis. Interestingly, each local RAS has a distinct enzymatic profile resulting in different patterns of angiotensin fragment generation in different tissues. A better understanding of the autocrine and paracrine mechanisms involved in the renal RAS and other local RASs might direct future organ-specific therapy.

Key Points

  • Intrarenal levels of angiotensin II and other angiotensin peptides are considerably higher than those in plasma; both glomerular and tubular compartments of the kidney possess an intrinsic local renin–angiotensin system

  • Upregulation of the intrarenal renin–angiotensin system has been linked with the pathogenesis of various models of proteinuric kidney diseases including diabetic and hypertensive glomerulopathies

  • Intrarenal angiotensin-converting enzyme 2 activity seems to counterbalance the actions of angiotensin-converting enzyme by converting angiotensin II to angiotensin-(1–7), a peptide that primarily antagonizes the angiotensin II type 1 receptor-mediated antinatriuretic, pressor and profibrotic effects of angiotensin II, presumably through activation of the mas receptor

  • Aminopeptidase A and neprilysin are peptidases that are highly expressed in the kidney and have an important role in the intrarenal metabolism of angiotensin I and angiotensin II

  • The binding of renin to the prorenin receptor constitutes a novel mechanism that activates the intrarenal renin–angiotensin system; this finding implies that angiotensin-II-independent mechanisms of tissue injury might exist

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Figure 1: A contemporary view of the synthesis and metabolism of angiotensin and related peptides.
Figure 2: Expression of angiotensin-II-forming and angiotensin-II-degrading or converting enzymes in (A) resident renal cells, (B) cells in the renal vasculature (i.e. endothelial and vascular smooth muscle cells), and (C) infiltrating cell types (i.e. mast cells, macrophages and neutrophils) that have been identified in certain kidney diseases.

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Acknowledgements

The author thanks Dr John R Raymond and Dr Michael G Janech for valuable discussions and collaborations. The author is supported by the Dialysis Clinics Inc. Paul Teschan Research Fund.

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  1. Division of Nephrology, 96 Jonathan Lucas Street, Clinical Science Building, Room 829, Medical University of South Carolina, Charleston, SC 29425, USA velezj@musc.edu

Authors and Affiliations

  1. JCQ Velez is Assistant Professor in the Division of Nephrology at the Medical University of South Carolina, and Associate Investigator in the VA Research Enhancement Award Program, Ralph H Johnson VA Medical Center, Charleston, SC, USA.,

    Juan Carlos Q Velez

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The author has declared an association with the following company: Novartis Pharmaceuticals (speakers bureau: honoraria).

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Velez, J. The importance of the intrarenal renin–angiotensin system. Nat Rev Nephrol 5, 89–100 (2009). https://doi.org/10.1038/ncpneph1015

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