Mederle, Katharina and Schweda, Frank and Kattler, Veronika and Doblinger, Elisabeth and Miyata, Keishi and Hoecherl, Klaus and Oike, Yuichi and Castrop, Hayo (2013) The angiotensin II AT1 receptor-associated protein Arap1 is involved in sepsis-induced hypotension. CRITICAL CARE, 17 (4): R130. ISSN 1466-609X, 1364-8535
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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 a and interferon gamma. 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BLOOD-PRESSURE; TUBULOGLOMERULAR FEEDBACK; PLASMA-MEMBRANE; MICE LACKING; IN-VITRO; SYSTEM; KIDNEY; ATRAP; PHOSPHORYLATION; INFLAMMATION; |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Wolf Hayo Castrop |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 28 Apr 2020 08:13 |
| Last Modified: | 28 Apr 2020 08:13 |
| URI: | https://pred.uni-regensburg.de/id/eprint/17316 |
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