Duchenne muscular dystrophy is a severe, progressive, muscle-wasting disease that leads to difficulties with movement and, eventually, to the need for assisted ventilation and premature death. The disease is caused by mutations in DMD (encoding dystrophin) that abolish the production of dystrophin in muscle. Muscles without dystrophin are more sensitive to damage, resulting in progressive loss of muscle tissue and function, in addition to cardiomyopathy. Recent studies have greatly deepened our understanding of the primary and secondary pathogenetic mechanisms. Guidelines for the multidisciplinary care for Duchenne muscular dystrophy that address obtaining a genetic diagnosis and managing the various aspects of the disease have been established. In addition, a number of therapies that aim to restore the missing dystrophin protein or address secondary pathology have received regulatory approval and many others are in clinical development.

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Duchenne muscular dystrophy.

The consequences of cerebrovascular disease are among the leading health issues worldwide. Large and small cerebral vessel disease can trigger stroke and contribute to the vascular component of other forms of neurological dysfunction and degeneration. Both forms of vascular disease are driven by diverse risk factors, with hypertension as the leading contributor. Despite the importance of neurovascular disease and subsequent injury after ischemic events, fundamental knowledge in these areas lag behind our current understanding of neuroprotection and vascular biology in general. The goal of this review is to address select key structural and functional changes in the vasculature that promote hypoperfusion and ischemia, while also affecting the extent of injury and effectiveness of therapy. In addition, as damage to the blood–brain barrier is one of the major consequences of ischemia, we discuss cellular and molecular mechanisms underlying ischemia-induced changes in blood–brain barrier integrity and function, including alterations in endothelial cells and the contribution of pericytes, immune cells, and matrix metalloproteinases. Identification of cell types, pathways, and molecules that control vascular changes before and after ischemia may result in novel approaches to slow the progression of cerebrovascular disease and lessen both the frequency and impact of ischemic events.

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Chronic activation of the renin-angiotensin-aldosterone system (RAAS) promotes and perpetuates the syndromes of congestive heart failure, systemic hypertension, and chronic kidney disease. Excessive circulating and tissue angiotensin II (AngII) and aldosterone levels lead to a pro-fibrotic, -inflammatory, and -hypertrophic milieu that causes remodeling and dysfunction in cardiovascular and renal tissues. Understanding of the role of the RAAS in this abnormal pathologic remodeling has grown over the past few decades and numerous medical therapies aimed at suppressing the RAAS have been developed. Despite this, morbidity from these diseases remains high. Continued investigation into the complexities of the RAAS should help clinicians modulate (suppress or enhance) components of this system and improve quality of life and survival. This review focuses on updates in our understanding of the RAAS and the pathophysiology of AngII and aldosterone excess, reviewing what is known about its suppression in cardiovascular and renal diseases, especially in the cat and dog.

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The renin-angiotensin-aldosterone system and its suppression.

Importance of the brain corticosteroid receptor balance in metaplasticity, cognitive performance and neuro-inflammation.

Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis

The mineralocorticoid receptor (MR) and its ligand aldosterone are the principal modulators of hormone-regulated renal sodium reabsorption. In addition to the kidney, there are several other cells and organs expressing MR, in which its activation mediates pathologic changes, indicating potential therapeutic applications of pharmacological MR antagonism. Steroidal MR antagonists have been used for decades to fight hypertension and more recently heart failure. New therapeutic indications are now arising, and nonsteroidal MR antagonists are currently under development. This review is focused on nonclassic MR targets in cardiac, vascular, renal, metabolic, ocular, and cutaneous diseases. The MR, associated with other risk factors, is involved in organ fibrosis, inflammation, oxidative stress, and aging; for example, in the kidney and heart MR mediates hormonal tissue-specific ion channel regulation. Genetic and epigenetic modifications of MR expression/activity that have been documented in hypertension may also present significant risk factors in other diseases and be susceptible to MR antagonism. Excess mineralocorticoid signaling, mediated by aldosterone or glucocorticoids binding, now appears deleterious in the progression of pathologies that may lead to end-stage organ failure and could therefore benefit from the repositioning of pharmacological MR antagonists.

https://pharmrev.aspetjournals.org/content/pharmrev/68/1/49.full.pdf

N. Farman

Papers

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology