Research Article
A mechanism for mineralocortcoid participation in renal disease and heart failure

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Abstract

Various forms of chronic renal disease as well as congestive heart failure progress irrespective of currently available supportive care. Clinical evidence indicates that blockade of the renin–angiotensin system and/or mineralocorticoid inhibition are partially effective. Recently, it was suggested that the initiation of feed–forward intracrine loops such as renin–angiotensin system up–regulation can explain the progression of disease in the face of the control of initiating factors such as high glucose or hypertension. Here, these notions are expanded to include a potential interaction of mineralocorticoid activity with intracrine renin–angiotensin system up–regulation. In addition to suggesting therapeutic interventions, these observations lead to an expanded view of intracrine physiology.

Introduction

This laboratory and others have extensively studied the intracellular action of the peptide hormone angiotensin II. These studies, as well as those of other peptides carried out in other laboratories, led us to develop principles of intracrine action—that is, principles derived from the study of the regulation, intercellular trafficking (following secretion, atypical secretion, via exosomes, or possibly via nanotubes), and intracellular actions of extracellular signaling proteins we have termed intracrines.1, 2, 3, 4, 5, 6, 7, 8, 9 Included in this group are hormones, cytokines, growth factors, DNA binding proteins, enzymes, and other moieties. Of note, components of the renin–angiotensin system (RAS) such as (pro)renin, angiotensin–converting enzyme, angiotensin II, and angiotensin (1–7) are intracrines. Principles of intracrine action, such as their tendency to participate in feed–forward regulatory loops leading to their up–regulation or up–regulation of their signaling pathways, have been defined. Although feedback loops are commonly recognized regulators of biological systems, feed–forward loops of various sorts are also important biological regulators. The Pavlovian conditioned salivary reflex is an example of a feed–forward regulatory loop in that a stimulus temporally associated with food (input) triggers salivation (output) in advance of food presentation.10 Closed feed–forward loops in which outputs up–regulate inputs also occur, leading to self–sustaining loops, as in the case of a variety of intracrines.1, 2, 3, 4, 5, 6, 7, 8, 9 Intracrine action permits the development of an active form of differentiation by which intracrines can spread from one cell to a target cell, up–regulate intracrine action in that cell, and thereby establish a self–sustaining intracrine loop in that cell—a loop that will persist even when the extracelluar intracrine is removed. The target cell is thus placed in a new differentiated or altered physiological state. Intercellular intracrine trafficking then permits the physiologic alteration to spread in a tissue. Canonical intracrine action (action at a traditional receptor) and non–canonical action (action in the absence of a traditional receptor) have been defined. These notions have been reviewed in detail elsewhere.1, 2, 3, 4, 5, 6, 7, 8, 9

Section snippets

Cardiorenal Disease

Chronic renal diseases of various types and systolic congestive heart failure are progressive diseases that frequently progress even when an initiating cause is removed or mitigated. For example, blood pressure control and glucose control slow the progression of diabetic nephropathy but only partially. The disease continues to progress. Because the local RAS has been shown to be up–regulated in many of these disorders, we have suggested that the production of progressive intracrine pathologic

Mineralocorticoid Participation

In investigating the possible role of aldosterone in the progression of cardiorenal disease, the results of the Siragy group are instructive.14, 15 They demonstrated that aldosterone was synthesized in kidney cortex, was stimulated by angiotensin II and low salt, and was also up–regulated by high glucose. The angiotensin receptor blocker valsartan largely blocked this aldosterone up–regulation, indicating that it was angiotensin–driven. Moreover, when glucose was normalized in diabetic animals

Atypical MR Activation

A potential objection to this proposal comes from the observation that, in clinical trials of MRAs, circulating aldosterone levels were low (possibly in part because of the use of converting enzyme inhibitors or angiotensin receptor blockers in patients with congestive heart failure) and yet the MR antagonists were therapeutically beneficial.26, 27, 28, 29, 30, 31 In an experimental model, cortisol in the heart paradoxically appears to bind and inactivate MR, protecting the myocardium from

Conclusion

Considerable evidence supports a therapeutic role for blockade of the RAS and for MRA in chronic renal disease and systolic congestive heart failure.11, 12, 13, 28, 29, 30, 31 Here, it is argued that local feed–forward intracrine loops support the progression of pathology in these disorders and that, in this process, mineralocorticoid up–regulation and/or MR activation participates both in the production of pathology and in the maintenance of intracrine feed–forward loops. The possibility that

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    This work was funded by Ochsner Clinic Foundation.

    Conflict of interest: none.

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