Aminopeptidases in Cardiovascular and Renal Function. Role as Predictive Renal Injury Biomarkers

Abstract

Aminopeptidases (APs) are metalloenzymes that hydrolyze peptides and polypeptides by scission of the N-terminus amino acid and that also participate in the intracellular final digestion of proteins. APs play an important role in protein maturation, signal transduction, and cell-cycle control, among other processes. These enzymes are especially relevant in the control of cardiovascular and renal functions. APs participate in the regulation of the systemic and local renin–angiotensin system and also modulate the activity of neuropeptides, kinins, immunomodulatory peptides, and cytokines, even contributing to cholesterol uptake and angiogenesis. This review focuses on the role of four key APs, aspartyl-, alanyl-, glutamyl-, and leucyl-cystinyl-aminopeptidases, in the control of blood pressure (BP) and renal function and on their association with different cardiovascular and renal diseases. In this context, the effects of AP inhibitors are analyzed as therapeutic tools for BP control and renal diseases. Their role as urinary biomarkers of renal injury is also explored. The enzymatic activities of urinary APs, which act as hydrolyzing peptides on the luminal surface of the renal tubule, have emerged as early predictive renal injury biomarkers in both acute and chronic renal nephropathies, including those induced by nephrotoxic agents, obesity, hypertension, or diabetes. Hence, the analysis of urinary AP appears to be a promising diagnostic and prognostic approach to renal disease in both research and clinical settings.

Effects of Virgin Olive Oil on Blood Pressure and Renal Aminopeptidase Activities in Male Wistar Rats

“…Within these local systems, angiotensin peptides are metabolized by various enzymes of the aminopeptidase (AP) family, also called angiotensinases, and previous results of our research group have shown that the activities of these peptidases are affected by the type of fatty acids consumed with the diet [5,14,25,26]. These APs are relevant in the control of blood pressure (BP) and renal function, participating in the regulation of the systemic and local RAS, but also like predictive renal injury biomarkers on the luminal surface of the renal tubule [27,28]. It has been suggested that several of the AP activities involved in angiotensin metabolism in renal and cardiovascular tissues of the rat may be modified depending on the amount and type of fat in the diet [15].…”

A short ERAP2 that binds IRAP is expressed in macrophages independently from gene variation

“…In addition, it has been shown to be involved in several other functions, ranging from the insulin metabolic pathway to vesicular trafficking and even in cognitive processes (7,8). Furthermore, the three genes have been found associated with autoimmune and inflammatory conditions, hypertension, and cancer (2,(9)(10)(11)(12)(13)(14)(15). Since they are regulators of the Renin-Angiotensin system (RAS), their imbalance can have indeed consequences on different aspects of the associated pathologies (16)(17)(18).…”

High-Fat Diets Modify the Proteolytic Activities of Dipeptidyl-Peptidase IV and the Regulatory Enzymes of the Renin–Angiotensin System in Cardiovascular Tissues of Adult Wistar Rats

“…Within these local RAS, the type of fatty acids consumed with the diet allows modifying various enzymes of the aminopeptidase (AP) family, also called angiotensinases, responsible for metabolizing angiotensin peptides (Ang) [ 5 , 9 , 26 ]. The APs are relevant in the control of BP and cardiac function [ 6 , 27 ], participating in the regulation of systemic and local RAS, but also as predictive biomarkers of functionality in different organs, including the heart [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. It is suggested that several of the activities of APs involved in the metabolism of angiotensin in the cardiovascular tissues of the rat can be modified according to the amount and type of fat in the diet [ 6 ].…”

“…Along with angiotensinases, there are other APs such as leucyl-AP (LeuAP; EC 3.4.11.1) and gamma-glutamyl transferase (GGT; EC 2.3.2.2) involved in the control of BP that act as functional markers of cardiovascular risk [ 7 , 9 , 58 ] and that are associated with different cardiovascular and kidney diseases [ 34 , 54 ]. GGT is an enzyme of glutathione and cysteine (Cys) metabolism with pro-oxidant activity and a modulating influence on endothelial dysfunction [ 59 ].…”