Mineralocorticoid Receptor Signaling as a Therapeutic Target for Renal and Cardiac Fibrosis

Abstract

Activation of the mineralocorticoid receptor (MR) plays important roles in both physiological and pathological events. Blockade of MR signaling with MR antagonists (MRAs) has been used clinically to treat kidney and cardiac disease associated with hypertension and other chronic diseases, resulting in suppression of fibrosis in these organs. However, the current use of steroidal MRAs has been limited by off target effects on other hormone receptors or adverse effects on kidney tubular function. In this review, we summarize recent insights into the profibrotic roles of MR signaling in kidney and cardiovascular disease. We review experimental in vitro data identifying the pathological mechanisms associated with MR signaling in cell types found in the kidney (mesangial cells, podocytes, tubular cells, macrophages, interstitial fibroblasts) and heart (cardiomyocytes, endothelial cells, vascular smooth muscle cells, macrophages). In addition, we demonstrate the in vivo importance of MR signaling in specific kidney and cardiac cell types by reporting the outcomes of cell type selective MR gene deletion in animal models of kidney and cardiac disease and comparing these findings to those obtained with MRAs treatment. This review also includes a discussion of the potential benefits of novel non-steroidal MRAs for targeting kidney and cardiac fibrosis compared to existing steroidal MRAs, as well as the possibility of novel combination therapies and cell selective delivery of MRAs.

Bone marrow-derived cells and their conditioned medium induce microvascular repair in uremic rats by stimulation of endogenous repair mechanisms

“…These cells are not normally found in the healthy myocardium, but are the most prevalent cell type in the infarct scar, given that transient activation of myofibroblasts is part of the normal wound healing process 48 , 49 . Despite the cell infiltrate with myofibroblast-like phenotype and high aldosterone levels (pro-fibrotic effects) 41 , 42 , the hearts of rats that were treated with BMDC or CM displayed a diminished extent of fibrosis compared with those treated with the vehicle, suggesting that the activation of these cells should be transient and contributes to beneficial remodeling instead of fibrosis formation. Moreover, reduced fibrosis formation observed in these animals might also be partially due to the preservation of the microvascular integrity by BMDC and CM treatments 50 .…”

Safety, Tolerability, and Pharmacokinetics of the Mineralocorticoid Receptor Modulator AZD9977 in Healthy Men: A Phase I Multiple Ascending Dose Study

“…7,8 The endogenous agonists aldosterone and cortisol activate the MR, 7 a member of the nuclear receptor subfamily, which is expressed in the cardiovascular system, the kidneys, and the central nervous system, as well as in adipose and other tissues. 8 In nonepithelial tissues, MR activation promotes inflammation, oxidative stress, fibrosis, and endothelial dysfunction, leading to cardiovascular and renal injury. 7,8 Physiologically, the MR plays a central role in regulation of blood pressure as well as fluid and electrolyte balance.…”

“…8 In nonepithelial tissues, MR activation promotes inflammation, oxidative stress, fibrosis, and endothelial dysfunction, leading to cardiovascular and renal injury. 7,8 Physiologically, the MR plays a central role in regulation of blood pressure as well as fluid and electrolyte balance. 9,10 In kidney epithelial cells, MR activation increases sodium resorption in the renal tubule, which results in concomitant water retention and potassium secretion.…”

“…Excessive mineralocorticoid receptor (MR) activation is a central factor in the pathophysiology of both heart failure and CKD . The endogenous agonists aldosterone and cortisol activate the MR, a member of the nuclear receptor subfamily, which is expressed in the cardiovascular system, the kidneys, and the central nervous system, as well as in adipose and other tissues . In nonepithelial tissues, MR activation promotes inflammation, oxidative stress, fibrosis, and endothelial dysfunction, leading to cardiovascular and renal injury .…”

Extra-cellular matrix induced by steroids through a G-protein coupled receptor in a Drosophila model of renal fibrosis

“…TGF-β1 contributes to fibrosis by activating myofibroblasts (5) as well as through suppressing matrix metalloproteinases, which can further promote excess extra-cellular matrix (6). Aldosterone affects these processes through its interaction with the mineralocorticoid nuclear hormone receptor (MR), as inferred from studies where blockade of MR activity prevents aldosterone-associated inflammatory and fibrotic outcomes (7–9).…”