Dipeptidyl peptidase 3 modulates the renin–angiotensin system in mice

Abstract

Dipeptidyl peptidase 3 (DPP3) is a zinc-dependent hydrolase involved in degrading oligopeptides with 4–12 amino acid residues. It has been associated with several pathophysiological processes, including blood pressure regulation, pain signaling, and cancer cell defense against oxidative stress. However, the physiological substrates and the cellular pathways that are potentially targeted by DPP3 to mediate these effects remain unknown. Here, we show that global DPP3 deficiency in mice (DPP3-/-) affects the renin–angiotensin system (RAS). LC-MS–based profiling of circulating angiotensin peptides revealed elevated levels of angiotensin II, III, IV, and 1–5 in DPP3-/- mice, while blood pressure, renin activity, and aldosterone levels remained unchanged. Activity assays using the purified enzyme confirmed that angiotensin peptides are substrates for DPP3. Aberrant angiotensin signaling was associated with substantially higher water intake and increased renal reactive oxygen species (ROS) formation in the kidneys of DPP3-/- mice. The metabolic changes and altered angiotensin levels observed in male DPP3-/- mice were either absent or attenuated in female DPP3-/- mice, indicating sex-specific differences. Taken together, our observations suggest that DPP3 regulates the RAS pathway and water homeostasis by degrading circulating angiotensin peptides.

Alteration of the Renin–Angiotensin–Aldosterone System in Shock: Role of the Dipeptidyl Peptidase 3

“…DPP3 is a zinc-dependent metalloprotease that cleaves the N-terminal extremity of various bioactive peptides, including angiotensins, enkephalins, and endorphins ( 4 ). Interestingly, although DPP3 hydrolyzes angiotensin II into angiotensin IV, it has no direct effect on angiotensin I, thus leading to an increased angiotensin I/angiotensin II ratio, consistent with Bellomo and colleagues’ findings ( 5 , 6 ). Under these conditions, as pointed out by the authors, decreased AT1R stimulation then triggers the production of renin.…”

Promotion of vascular integrity in sepsis through modulation of bioactive adrenomedullin and dipeptidyl peptidase 3

“…Multiple studies had already pointed out the putative rapid angiotensin-scavenging properties of DPP3 based on in vitro experiments [18]. Angiotensin II, angiotensin III, angiotensin IV, angiotensin 1-5 and angiotensin 1-7 were all found to be effectively hydrolysed by DPP3 [17,18,44], with angiotensin IV (six amino acids in length) being hydrolysed ten times faster than angiotensin II (eight amino acids in length) [21]. However, as reliable assays to measure cDPP3 were not available, these findings could not be confirmed in vivo.…”

“…Of note, DPP3 infusion reduced circulating angiotensin II levels to even lower levels than baseline, suggesting that endogenously produced angiotensin II was also effectively cleaved. In DPP3 (À/À) knockout mice, significant upregulation of the classical RAAS was observed, reflected by higher circulating levels of angiotensin II, angiotensin III, angiotensin IV and angiotensin 1-5, all known substrates of DPP3 [17].…”

“…Targeted interventions aimed at improving endothelial barrier function and vascular tone may prove highly relevant in this regard [8]. In this review, we focus on dipeptidyl peptidase 3 (DPP3), an ubiquitous cytosolic enzyme involved in the degradation of several important signalling molecules essential for regulation of vascular tone, including angiotensin II [17,18], and adrenomedullin (ADM), a key hormone involved in the regulation of vascular tone and endothelial barrier function [19]. We describe the general vascular properties of DPP3 and ADM and provide an overview of the current understanding of the different roles of these molecules in sepsis and septic shock.…”

Plasma proenkephalin A 119–159 and dipeptidyl peptidase 3 on admission after cardiac arrest help predict long-term neurological outcome

“…19,20 Recently, in vivo studies reported that global DPP3 deficiency in mice affects the concentrations of the renin-angiotensin-aldosterone system (RAAS) peptides strengthening previous findings showing a constitutive presence of DPP3 in healthy human blood. 21,22 In disease, high plasma circulating DPP3 (cDPP3) levels have been found in sepsis, cardiogenic shock and vasodilatory shock, where cDPP3 is associated with organ failure and mortality. 22,23 Adrenomedullin (ADM) is a 52-amino acid peptide with vasoactive properties and expressed in numerous tissues.…”