title: Chronic p38 mitogen-activated protein kinase inhibition improves vascular function and remodeling in angiotensin II-dependent hypertension.
abstract: BACKGROUND
  An excess of angiotensin II (Ang II) causes hypertension and vascular injury. Activation of mitogen-activated protein kinase p38 (p38-MAPK) plays a substantial role in Ang II-dependent organ damage. Recently, we showed that p38-MAPK activation regulates the pressor response to Ang II. This study evaluates the effect of chronic p38-MAPK inhibition in Ang II-dependent hypertension.
  
  
  METHODS
  C57Bl/6J mice were infused with Ang II for 14 days and either treated with the p38-MAPK inhibitor BIRB796 (50 mg/kg/day) or the vehicle as the control. We assessed vascular function in the aorta and isolated perfused kidneys.
  
  
  RESULTS
  Chronic p38-MAPK inhibition did not alter blood pressure at the baseline, but attenuated Ang II-induced hypertension significantly (baseline: 122 ± 2 versus 119 ± 4 mmHg; Ang II: 173 ± 3 versus 155 ± 3 mmHg; p < 0.001). In addition, BIRB796 treatment improved vascular remodeling by reducing the aortic media-to-lumen ratio and decreasing the expression of the membrane metalloproteinases (MMP) MMP-1 and MMP-9. Moreover, renal vascular dysfunction induced by chronic Ang II infusion was significantly ameliorated in the BIRP796-treated mice. Acute p38-MAPK inhibition also improved vascular function in the aorta and kidneys of Ang II-treated mice, highlighting the important role of p38-MAPK activation in the pathogenesis of vascular dysfunction.
  
  
  CONCLUSIONS
  Our findings indicated there is an important role for p38-MAPK in regulating blood pressure and vascular injury, and highlighted its potential as a pharmaceutical target.
authors.affiliation: Department of Nephrology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: S A
authors.initials: SA
authors.lastname: Potthoff
authors.affiliation: Department of Nephrology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Stamer
authors.affiliation: Department of Nephrology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Grave
authors.affiliation: Department of Nephrology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Königshausen
authors.affiliation: Department of Nephrology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: S H
authors.initials: SH
authors.lastname: Sivritas
authors.affiliation: Department of Nephrology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Thieme
authors.affiliation: Department of Nuclear Medicine, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: Y
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Department of Nephrology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Woznowski
authors.affiliation: Department of Nephrology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: L C
authors.initials: LC
authors.lastname: Rump
authors.affiliation: Department of Nephrology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany johannes.stegbauer@med.uni-duesseldorf.de.
authors.forename: J
authors.initials: J
authors.lastname: Stegbauer
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects; D006973:Hypertension / Q000201:enzymology / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D010477:Perfusion; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D013599:Systole / Q000187:drug effects; D066253:Vascular Remodeling / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D000804:Angiotensin II; D026422:S-Nitrosoglutathione; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Angiotensin II; animal study; blood pressure; hypertension; kidney; mice; mitogen-activated protein kinase; vascular dysfunction