Structure and functions of angiotensinogen

Abstract

Angiotensinogen (AGT) is the sole precursor of all angiotensin peptides. Although AGT is generally considered as a passive substrate of the renin-angiotensin system, there is accumulating evidence that the regulation and functions of AGT are intricate. Understanding the diversity of AGT properties has been enhanced by protein structural analysis and animal studies. In addition to whole-body genetic deletion, AGT can be regulated in vivo by cell-specific procedures, adeno-associated viral approaches and antisense oligonucleotides. Indeed, the availability of these multiple manipulations of AGT in vivo has provided new insights into the multifaceted roles of AGT. In this review, the combination of structural and functional studies is highlighted to focus on the increasing recognition that AGT exerts effects beyond being a sole provider of angiotensin peptides.

Figure 1

The renin–angiotensin cascade. Angiotensinogen is the substrate, and renin is its direct enzyme to generate all downstream angiotensin peptides. Numbers in parenthesis represent residue numbered starting from the N-terminus. ‘aa' denotes ‘amino acid'.

Figure 2

Sequence conversation of AngII across species. Blue color represents conserved residues across species.

Figure 3

Conservation of surface residues in the core serpin domain of AGT. Sequences from human, rat, mouse, xenopus and zebrafish were aligned, and conservation was mapped on the surface of the protein (PDB 2X0B) using Consurf. Patches of pink residues indicate highly conserved regions, often important for physical interactions. In particular, the distal face, which has no assigned function, has significant regions of conservation.

Figure 4

Global AGT-deficient mouse has severe impairment of kidney development. Wild-type and AGT−/− littermates are male and aged 8 weeks. AGT−/− mouse has hydronephrosis (left kidney).