Multidisciplinary Investigation from UPMC Children’s Examines Role of CCL5 and CCR5 in Aldosterone-Induced Hypertension and Vascular Dysfunction

A recent study conducted by a multidisciplinary team from UPMC Children's Hospital of Pittsburgh and the University of Pittsburgh was featured as the cover article in the April edition of the journal Hypertension.

The study, called “Role of the CCL5 and Its Receptor, CCR5, in the Genesis of Aldosterone-Induced Hypertension, Vascular Dysfunction, and End-Organ Damage,” focuses on the influence of the chemokine ligand CCL5 and its receptor CCR5 on hypertension and vascular damage induced by aldosterone.

The study was led by first author Rafael M. Costa, PhD, and senior author Thiago Bruder-Nascimento, PhD, principal investigator of the Bruder Lab for Vascular Biology and Metabolic Diseases at UPMC Children’s.

Contributing to the study from the Division of Pediatric Nephrology at UPMC Children’s were, Débora M. Cerqueira, PhD, and division chief, Jacqueline Ho, MD, MS.

Other entities contributing to this research were the Center for Pediatrics Research in Obesity and Metabolism (CPROM) at UPMC Children’s, the Division of Cardiology at the University of Pittsburgh, the Vascular Medicine Institute, the Department of Pharmacology and Chemical Biology, and the Department of Immunology.

About the Research: Findings and Clinical Implications

Aldosterone is a steroid hormone produced by the adrenal glands, primarily known for its role in regulating sodium and potassium balance in the body, which in turn affects blood volume and blood pressure. However, beyond its classic role in electrolyte and water balance, aldosterone has significant implications for cardiovascular health, particularly through its ability to exacerbate vascular inflammation, leading to serious health complications. Aldosterone functions by binding to mineralocorticoid receptors (MRs), which are present in kidney cells and in various other tissues, including vascular endothelial cells and smooth muscle cells. Once activated, these receptors can influence gene expression and influence cellular functions.

Until now, the specific mechanisms through which aldosterone mediates these effects were poorly understood. The study from UPMC Children’s provides new insights by exploring the roles of CCL5 and CCR5, which are more commonly associated with immune responses in infectious diseases.

The research utilized CCR5 positive (CCR5+/+) and knockout (CCR5−/−) mice, which were administered aldosterone along with a saline solution over a two-week period. The team observed significant increases in blood pressure, vascular dysfunction, and renal damage in CCR5+/+ mice, all of which were markedly reduced in CCR5−/− mice. The protective effects in the knockout mice were linked to the absence of the CCL5/CCR5 interaction.

Through the research, the team found that CCL5 stimulates the expression of NOX1 and NFκB, leading to increased oxidative stress and inflammation, while reducing nitric oxide production in endothelial cells. These adverse effects were mitigated by blocking CCR5 with the drug Maraviroc, suggesting a new therapeutic pathway for managing hypertension induced by aldosterone excess. Both NOX1 and NFκB are critical to understanding the cellular mechanisms underlying diseases like hypertension, where their regulation or dysregulation can significantly affect disease progression or treatment outcomes.

This study contributes to understanding the molecular pathways by which aldosterone exacerbates vascular and renal conditions and highlights the therapeutic potential of targeting CCL5 and CCR5 in conditions characterized by excess aldosterone.

Read more about the study and its findings using the reference link below.

Reference

Costa RM, Cerqueira DM, Bruder-Nascimento A, Alves JV, Awata WMC, Singh S, Kufner A, Prado DS, John E, Cifuentes-Pagano E, Hawse WF, Dutta P, Pagano PJ, Ho J, Bruder-Nascimento T. Role of the CCL5 and Its Receptor CCR5, in the Genesis of Aldosterone-Induced Hypertension, Vascular Function, and End-Organ Damage. Hypertension. 2024 Apr; 81(4): 776-786.