A redox switch in angiotensinogen modulates angiotensin release

Abstract

Blood pressure is critically controlled by angiotensins1, vasopressor peptides specifically released by the enzyme renin from the tail of angiotensinogen, a non-inhibitory member of the serpin family of protease inhibitors2,3. Although angiotensinogen has long been regarded as a passive substrate, the crystal structures solved here to 2.1Å resolution show that the angiotensin cleavage-site is inaccessibly buried in its amino-terminal tail. The conformational rearrangement that makes this site accessible for proteolysis is revealed in a 4.4Å structure of the complex of human angiotensinogen with renin. The co-ordinated changes involved are seen to be critically linked by a conserved but labile disulphide bridge. We show that the reduced unbridged form of angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidised sulphydryl-bridged form, which preferentially interacts with receptor-bound renin. We propose that this redox-responsive transition of angiotensinogen to a form that will more effectively release angiotensin at a cellular level contributes to the modulation of blood pressure. Specifically, we demonstrate the oxidative switch of angiotensinogen to its more active sulphydryl-bridged form in the maternal circulation in pre-eclampsia - the hypertensive crisis of pregnancy that threatens the health and survival of both mother and child.

Single Nucleotide Polymorphisms in G Protein Signaling Pathway Genes in Preeclampsia

“…Other mechanisms, that have been proposed to result in increased Ang II responsiveness in preeclampsia include activating autoantibodies against the AT1-receptor, 28 heterodimerization of AT1-and Bradykinin-receptors, 31 and a redox state of angiotensinogen. 32 The presence of the rs4606 CG or GG genotype of RGS2 could possibly result in interactions with these, or other yet unknown, mechanisms.…”

Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders

“…A recent report suggests that angiotensinogen is cleaved differently by free renin and renin bound to (P)RR. 110 Enzymatic activity of (P)RRbound renin is higher than free renin. Oxidized angiotensinogen more effectively releases Ang in the presence of renin bound to (P)RR.…”

“…Oxidized angiotensinogen more effectively releases Ang in the presence of renin bound to (P)RR. 110 The (P)RR is a fusion of two functionally distinct domains, a vertebrate-specific extracellular domain that is implicated in (pro)-renin binding and signaling, and the evolutionarily conserved or ancient transmembrane domain and a small intracellular tail, which are essential for cell survival. 27 The latter part (ancient segment) of the receptor (called M8.9), which is identical to the ATP6ap2 protein in sequence, co-precipitates with the v-H + -ATPase providing evidence for an association between the (P)RR and the enzyme.…”

Role of Biomarkers in Early Detection of Preeclampsia

“…Besides it, a novel form of oxidized angiotensinogen which enhances angiotensin formation, which was found in the circulation of PE subjects [24]. Surprisingly, circulating angiotensin II and aldosterone are suppressed in PE subjects.…”