Angiotensin Acetate

Renal osteodystrophy (ROD) is the core skeletal manifestation of chronic kidney disease mineral and skeletal disease (CKD-MBD), defined as a syndrome of abnormal bone metabolism, mineral homeostasis, and vascular calcification in CKD patients caused by progressive decline in renal function. Clinical data shows that over 80% of CKD stage 5 (dialysis) patients have varying degrees of ROD, with 40% of dialysis patients experiencing severe skeletal disorders after one year, manifested as bone pain, fractures, skeletal deformities, shortened height, and significantly increased risk of cardiovascular calcification, heart failure, and all-cause mortality.
The core pathological features of ROD include:

Disruption of calcium and phosphorus metabolism: hyperphosphatemia, hypocalcemia, and elevated calcium phosphorus product;
Abnormal metabolism of vitamin D: decreased activity of renal 1 α - hydroxylase and insufficient synthesis of active vitamin D3 (1,25- (OH) ₂ D3);
Secondary hyperparathyroidism (SHPT): excessive secretion of PTH drives enhanced bone resorption;
Imbalance in bone remodeling: decreased osteoblast activity, overactivation of osteoclasts, decreased bone mass, and destruction of bone microstructure;
Pathological remodeling of the bone kidney axis: Kidney injury and abnormal bone metabolism drive each other, forming a vicious cycle.

The Bone Kidney Axis is an endocrine network that connects bones and kidneys. Under physiological conditions, it maintains bone kidney homeostasis through calcium and phosphorus metabolism, vitamin D activation, PTH regulation, and bone derived factors (osteocalcin, FGF23).
Positive regulation of the bone kidney axis under physiological conditions
Kidney → Bone: Kidney 1 α - hydroxylase converts 25- (OH) D into 1,25- (OH) ₂ D3, promoting intestinal calcium absorption, osteoblast differentiation, and bone matrix mineralization; The kidneys excrete phosphorus and preserve calcium, maintain the balance of blood calcium and phosphorus, and inhibit excessive secretion of PTH.
Bones → kidneys: Osteoblasts secrete osteocalcin (OC), which regulates renal insulin sensitivity and calcium reabsorption; Osteocytes secrete fibroblast growth factor 23 (FGF23), which inhibits renal 1 α - hydroxylase activity, promotes phosphorus excretion, and forms negative feedback regulation.

The progression of CKD leads to irreversible damage to renal function, triggering pathological remodeling of the bone kidney axis, forming a vicious cycle of kidney injury → abnormal bone metabolism → worsening kidney injury:
Reduced renal function → phosphorus excretion disorder → hyperphosphatemia: hyperphosphatemia directly inhibits 1 α - hydroxylase, reduces 1,25- (OH) ₂ D3, and induces vascular calcification;
Low 1,25- (OH) ₂ D3 → decreased intestinal calcium absorption → hypocalcemia → excessive PTH secretion (SHPT);
High PTH → activation of osteoclasts → enhanced bone resorption → release of bone calcium → transient elevation of blood calcium → aggravation of renal calcium deposition;
Enhanced bone resorption → decreased bone mass, destruction of bone microstructure → progression of ROD;
High phosphorus, high PTH, low 1,25- (OH) ₂ D3 → Increased secretion of FGF23 by bone cells → Further inhibition of 1 α - hydroxylase → aggravation of vitamin D deficiency.

Traditionally, it is believed that RAAS only regulates blood pressure and water salt balance. However, recent studies have confirmed that RAAS (especially Ang II) is a core interaction factor in the bone kidney axis, expressed locally in both the kidney and bone. It directly regulates bone cell function, calcium and phosphorus metabolism, PTH secretion, and vitamin D activation through AT1/AT2 receptors.
As a high-purity, stable, and highly water-soluble exogenous Ang II preparation, angiotensin acetate is a core tool for studying the role of Ang II in the bone kidney axis and providing potential targets for ROD targeted interventions. Its role in ROD is concentration dependent, receptor subtype dependent, and microenvironment dependent:

High concentration (pathological grade, 10 ⁻⁸~10 ⁻⁶ mol/L): activates AT1 receptors, drives bone resorption, inhibits bone formation, exacerbates calcium phosphate disorders, promotes vascular calcification, and accelerates the progression of ROD;
Low concentration (physiological/reparative grade, 10 ⁻¹²~10 ⁻¹⁰ mol/L): activates AT2/Mas receptors, promotes bone formation, inhibits bone resorption, improves calcium and phosphorus metabolism, reduces vascular calcification, and exerts bone protective effects.

Ang II Acetate acts through AT1 receptor (AT1R), AT2 receptor (AT2R), and Mas receptor (MasR), with differential distribution and functional antagonism of the three major receptors in the bone kidney axis
AT1R: Highly expressed in the kidneys (tubules, mesangial cells, and periglomerular cells), bones (osteoclasts, osteoblasts, osteoblasts, chondrocytes), and parathyroid glands. High concentrations of Ang II preferentially bind (KD=1-5 nM), mediating pathological damage;

AT2R: Low expression in kidneys (interstitial cells, endothelial cells), bones (osteoblasts, bone cells, bone marrow mesenchymal stem cells), parathyroid glands, upregulated 5-10 times after injury, low concentration Ang II preferentially binds (KD=50-100nM), mediating repair and protection;
MasR: co expressed with AT2R in the kidneys, bones, and vascular endothelium, specifically binding to Ang 1-7 (Ang II degradation products) and synergistically amplifying the repair effect with AT2R.

The kidney is the main organ activated by RAAS, and during CKD, the local RAAS in the kidney is overactivated, leading to a significant increase in Ang II concentration
Generating site: Perispherical cells secrete renin → angiotensinogen is converted to Ang I → ACE catalyzes the generation of Ang II; Renal tubular epithelial cells, mesangial cells, and endothelial cells autocrine/paracrine Ang II;
Distribution characteristics: After intravenous infusion of Ang II Acetate, it preferentially accumulates in the renal cortex (renal tubules, glomeruli), with a concentration 2-3 times that of plasma, directly regulating renal calcium and phosphorus metabolism, 1 α - hydroxylase activity, and PTH sensitivity.

There is a complete local RAAS system in skeletal tissue, where osteoblasts, osteoclasts, bone cells, and bone marrow mesenchymal stem cells can all synthesize and secrete Ang II and its receptors, independently regulating bone metabolism from circulating RAAS
Osteoblasts: high expression of AT1R/AT2R, synthesis of Ang II, regulation of proliferation, differentiation, and bone matrix synthesis;
Osteoclasts: high expression of AT1R, low expression of AT2R, Ang II promotes differentiation, activation, and bone resorption through AT1R;
Bone cells: the most abundant bone cells, expressing AT1R/AT2R, secreting RANKL and FGF23, regulating bone remodeling and calcium phosphate metabolism;
Bone marrow-derived mesenchymal stem cells (MSCs) express AT2R, and low concentrations of Ang II promote osteogenic differentiation while inhibiting adipogenic differentiation.