AT2 receptor stimulation inhibits phosphate-induced vascular calcification

Kidney Int. 2019 Jan;95(1):138-148. doi: 10.1016/j.kint.2018.07.028. Epub 2018 Nov 12.


Vascular calcification is a common finding in atherosclerosis and in patients with chronic kidney disease. The renin-angiotensin system plays a role in the pathogenesis of cardiovascular remodeling. Here, we examined the hypothesis that angiotensin II type 2 receptor (AT2) stimulation has inhibitory effects on phosphate-induced vascular calcification. In vivo, calcification of the thoracic aorta induced by an adenine and high-phosphate diet was markedly attenuated in smooth muscle cell-specific AT2-overexpressing mice (smAT2-Tg) compared with wild-type and AT2-knockout mice (AT2KO). Similarly, mRNA levels of relevant osteogenic and vascular smooth muscle cell marker genes were unchanged in smAT2-Tg mice, while their expression was significantly altered in wild-type mice in response to high dietary phosphate. Ex vivo, sections of thoracic aorta were cultured in media supplemented with inorganic phosphate. Aortic rings from smAT2-Tg mice showed less vascular calcification compared with those from wild-type mice. In vitro, calcium deposition induced by high-phosphate media was markedly attenuated in primary vascular smooth muscle cells derived from smAT2-Tg mice compared with the two other mouse groups. To assess the underlying mechanism, we investigated the effect of PPAR-γ, which we previously reported as one of the possible downstream effectors of AT2 stimulation. Treatment with a PPAR-γ antagonist attenuated the inhibitory effects on vascular calcification observed in smAT2-Tg mice fed an adenine and high-phosphate diet. Our results suggest that AT2 activation represents an endogenous protective pathway against vascular calcification. Its stimulation may efficiently reduce adverse cardiovascular events in patients with chronic kidney disease.

Keywords: phosphate; renin angiotensin system; vascular calcification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / toxicity
  • Animals
  • Aorta, Thoracic / pathology
  • Aortic Diseases / blood
  • Aortic Diseases / drug therapy*
  • Aortic Diseases / etiology
  • Aortic Diseases / pathology
  • Cells, Cultured
  • Disease Models, Animal
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / pathology
  • PPAR gamma / antagonists & inhibitors
  • PPAR gamma / metabolism
  • Phosphates / blood
  • Phosphates / toxicity*
  • Primary Cell Culture
  • Receptor, Angiotensin, Type 2 / agonists
  • Receptor, Angiotensin, Type 2 / genetics
  • Receptor, Angiotensin, Type 2 / metabolism*
  • Renal Dialysis / adverse effects
  • Renal Insufficiency, Chronic / blood
  • Renal Insufficiency, Chronic / therapy
  • Vascular Calcification / blood
  • Vascular Calcification / drug therapy*
  • Vascular Calcification / etiology
  • Vascular Calcification / pathology


  • Agtr2 protein, mouse
  • PPAR gamma
  • Phosphates
  • Receptor, Angiotensin, Type 2
  • Adenine