The angiotensin II AT1 receptor-associated protein Arap1 is involved in sepsis-induced hypotension.

Abstract

INTRODUCTION:

Hypotension in septic patients results from hypovolemia, vasodilatation and hyporeactivity to vasoconstrictors, such as angiotensin II. The AT1 receptor-associated protein 1 (Arap1) is expressed in vascular smooth muscle cells and increases the surface expression of the AT1-receptor in vitro. We hypothesized that dysregulation of Arap1 may contribute to vascular hyporeactivity to angiotensin II during endotoxemia.

METHODS:

Arap1-deficient mice were used to assess the role of Arap1 in sepsis-induced hypotension. The isolated perfused kidney was used as an in vitro model to determine the relevance of Arap1 for vascular resistance and sensitivity to angiotensin II.

RESULTS:

During endotoxemia, mean arterial blood pressure (MAP) decreased in both genotypes, with the time course of sepsis-induced hypotension being markedly accelerated in Arap1-/- compared to +/+ mice. However, baseline MAP was similar in Arap1-/- and wildtype mice (102 ± 2 vs.103 ± 2 mmHg; telemetry measurements; n = 10; P = 0.66). Following lipopolysaccharide (LPS) injections (3 mg/kg), Arap1 expression was successively down-regulated in the wildtype mice, reaching levels below 10% of baseline expression. The endotoxemia-related decline in Arap1 expression could be recapitulated in cultured mesangial cells by incubation with pro-inflammatory cytokines, such as tumor necrosis factor α and interferon γ. Plasma renin concentration was increased in Arap1-/- mice compared to wildtype mice (66 ± 6 vs. 41 ± 4 ng AngI/ml/h; n = 23; P = 0.001), presumably contributing to preserved MAP under baseline conditions. The sensitivity of the vasculature to angiotensin II was reduced in Arap1-/- compared to +/+ mice, as determined in the isolated perfused kidney.

CONCLUSIONS:

Our data suggest that down-regulation of Arap1 expression during sepsis contributes to the development of hypotension by causing reduced vascular sensitivity to angiotensin II.

• Authors: Katharina Mederle, Frank Schweda, Veronika Kattler, Elisabeth Doblinger, Keishi Miyata, Klaus Höcherl, Yuichi Oike, Hayo Castrop
• Journal: Critical care (London, England) (Crit Care) Vol. 17 Issue 4 Pg. R130 (Jul 11 2013) ISSN: 1466-609X [Electronic] England
• PMID: 23844607 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Agtrap protein, mouse
• Lipopolysaccharides
• Renin

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Blood Pressure
• Down-Regulation
• Hypotension (etiology, metabolism)
• Kidney (metabolism)
• Lipopolysaccharides
• Male
• Mice
• Renin (metabolism)
• Renin-Angiotensin System (physiology)
• Sepsis (chemically induced, physiopathology)