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

Greg H Tesch,Morag J Young

doi:10.3389/fphar.2017.00313

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.

Highlights

The mineralocorticoid receptor (MR) is a ligand activated cytosolic receptor that has received increasing attention as a driver of cardiovascular and renal fibrosis
This suggests that the protective effects of MR blockade in heart and kidney can be achieved with finerenone at a dose that has reduced risk of hyperkalemia, which is proposed to be due to structural differences that influence its selective uptake in target tissues
Given the critical role of MR signaling in kidney and cardiac fibrosis, effective and selective targeting of the pathological effects of MR signaling in these organs remains a high priority for treatment

Summary

INTRODUCTION

The mineralocorticoid receptor (MR) is a ligand activated cytosolic receptor that has received increasing attention as a driver of cardiovascular and renal fibrosis. A potential explanation for the lack of effect of finerenone on potassium levels has been identified by radioactive labeling studies showing that finerenone is almost distributed in heart and kidney which contrasts with steroidal MRAs (spironolactone and eplerenone) which show greater accumulation in the kidney (Kolkhof et al, 2014) This suggests that the protective effects of MR blockade in heart and kidney can be achieved with finerenone at a dose that has reduced risk of hyperkalemia, which is proposed to be due to structural differences that influence its selective uptake in target tissues. This suggests that macrophage MR signaling may be the major cause of MR-mediated injury in CKD driven by macrophagedependent inflammation, which include progressive forms of glomerulonephritis and diabetic nephropathy

A Role for MR Signaling in Heart Failure

CONCLUSION