Advances in understanding the role of angiotensin-regulated proteins in kidney diseases

Introduction: Renin-angiotensin system (RAS) blockers are in clinical use to treat high blood pressure and proteinuric chronic kidney disease. However, RAS blockade is limited by the risk of hyperkalemia, angiotensin receptor blockers are not clinically superior to angiotensin-converting enzyme inhibitors and dual RAS blockade is formally contraindicated. Areas covered: We review the regulation of protein expression and activation by angiotensin II and RAS blockers as it contributes to kidney disease. Specifically excluded are direct renin actions as well as aldosterone actions. The search strategy included the terms angiotensin, protein, proteomics, inflammation, fibrosis, and kidney and was complemented by additional searches based on initial results. Expert commentary: Recent developments include an improved understanding of the structure, function, and signaling of angiotensin G-protein-coupled receptors; identification of ligands that behave as agonists, antagonists, and even reverse agonists on specific signaling and functional pathways of the same receptor; characterization of further signaling pathways by applying proteomics and phosphoproteomics; and systems biology approaches to characterize signatures of adequate RAS blockade or resistance of kidney injury to RAS blockade. These developments will allow optimization of clinical RAS targeting to improve kidney outcomes through precision nephrology strategies that may include combined approaches, along the path marked by clinically successful dual RAS/neprilysin blockade.