Tesch Greg H, Young Morag J
Department of Nephrology, Monash Health, ClaytonVIC, Australia.
Monash University Department of Medicine, Monash Health, ClaytonVIC, Australia.
Front Pharmacol. 2017 May 29;8:313. doi: 10.3389/fphar.2017.00313. eCollection 2017.
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 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 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.
盐皮质激素受体（MR）的激活在生理和病理过程中均发挥着重要作用。临床上已使用盐皮质激素受体拮抗剂（MRA）阻断MR信号传导来治疗与高血压及其他慢性疾病相关的肾脏和心脏疾病，从而抑制这些器官的纤维化。然而，目前甾体类MRA的使用受到对其他激素受体的脱靶效应或对肾小管功能的不良反应的限制。在本综述中，我们总结了近期关于MR信号传导在肾脏和心血管疾病中的促纤维化作用的见解。我们回顾了实验数据，这些数据确定了在肾脏（系膜细胞、足细胞、肾小管细胞、巨噬细胞、间质成纤维细胞）和心脏（心肌细胞、内皮细胞、血管平滑肌细胞、巨噬细胞）中发现的细胞类型中与MR信号传导相关的病理机制。此外，我们通过报告肾脏和心脏疾病动物模型中细胞类型选择性MR基因缺失的结果，并将这些发现与MRA治疗的结果进行比较，证明了MR信号传导在特定肾脏和心脏细胞类型中的重要性。本综述还讨论了新型非甾体类MRA与现有甾体类MRA相比在靶向肾脏和心脏纤维化方面的潜在益处，以及新型联合疗法和MRA细胞选择性递送的可能性。
