Prolylcarboxypeptidase deficiency is associated with increased blood pressure, glomerular lesions, and cardiac dysfunction independent of altered circulating and cardiac angiotensin II.

Autor: Maier C; Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Charité-Universitätsmedizin Berlin, Berlin, Germany., Schadock I; Max Delbrück Center for Molecular Medicine, Berlin, Germany., Haber PK; Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Charité-Universitätsmedizin Berlin, Berlin, Germany., Wysocki J; Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Ye M; Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Kanwar Y; Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Flask CA; Department of Radiology, Case Western Reserve University, Cleveland, OH, USA.; Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA., Yu X; Department of Radiology, Case Western Reserve University, Cleveland, OH, USA.; Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA., Hoit BD; Department of Medicine, Division of Cardiology, University Hospitals Case Medical Center and Case Western Reserve University, Cleveland, OH, USA., Adams GN; Department of Medicine, Division of Hematology and Oncology, University Hospitals Case Medical Center and Case Western Reserve University, Cleveland, OH, USA., Schmaier AH; Department of Medicine, Division of Hematology and Oncology, University Hospitals Case Medical Center and Case Western Reserve University, Cleveland, OH, USA., Bader M; Charité-Universitätsmedizin Berlin, Berlin, Germany.; Max Delbrück Center for Molecular Medicine, Berlin, Germany.; National Institute of Science and Technology in Nanobiopharmaceutics, Federal University of Minas Gerais, Belo Horizonte, Brazil.; German Center for Cardiovascular Research (DZHK), Berlin site, Berlin, Germany., Batlle D; Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. d-batlle@northwestern.edu.
Jazyk: angličtina
Zdroj: Journal of molecular medicine (Berlin, Germany) [J Mol Med (Berl)] 2017 May; Vol. 95 (5), pp. 473-486. Date of Electronic Publication: 2017 Feb 03.
DOI: 10.1007/s00109-017-1513-9
Abstrakt: Prolylcarboxypeptidase (PRCP) is a carboxypeptidase that cleaves angiotensin II (AngII) forming Ang(1-7). The impact of genetic PRCP deficiency on AngII metabolism, blood pressure (BP), kidney histology, and cardiac phenotype was investigated in two lines of PRCP-deficient mice: KST302 derived in C57BL/6 background and GST090 derived in FVB/N background. The GST090 line had increased mean arterial pressure (MAP) (113.7 ± 2.07 vs. WT 105.0 ± 1.23 mmHg; p < 0.01) and left ventricular hypertrophy (LVH) (ratio of diastolic left ventricular posterior wall dimension to left ventricular diameter 0.239 ± 0.0163 vs. WT 0.193 ± 0.0049; p < 0.05). Mice in the KST302 line also had mild hypertension and LVH. Cardiac defects, increased glomerular size, and glomerular mesangial expansion were also observed. After infusion of AngII to mice in the KST302 line, both MAP and LVH increased, but the constitutive differences between the gene trap mice and controls were no longer observed. Plasma and cardiac AngII and Ang(1-7) were not significantly different between PRCP-deficient mice and controls. Thus, PRCP deficiency is associated with elevated blood pressure and cardiac alterations including LVH and cardiac defects independently of systemic or cardiac AngII and Ang(1-7). An ex vivo assay showed that recombinant PRCP, unlike recombinant ACE2, did not degrade AngII to form Ang(1-7) in plasma at pH 7.4. PRCP was localized in α-intercalated cells of the kidney collecting tubule. The low pH prevailing at this site and the acidic pH preference of PRCP suggest a role of this enzyme in regulating AngII degradation in the collecting tubule where this peptide increases sodium reabsorption and therfore BP. However, there are other potential mechanisms for increased BP in this model that need to be considered as well. PRCP converts AngII to Ang(1-7) but only at an acidic pH. Global PRCP deficiency causes heart and kidney alterations and a moderate rise in BP. PRCP is abundant in the kidney collecting tubules, where the prevailing pH is low. In collecting tubules, PRCP deficiency could result in impaired AngII degradation. Increased AngII at this nephron site stimulates Na reabsorption and increases BP.
Key Message: Prolylcarboxypeptidase (PRCP) converts AngII to Ang (1-7) but only at an acidic pH. Global PRCP deficiency causes heart and kidney alterations and a moderate rise in BP. PRCP is abundant in the kidney collecting tubules, where the prevailing pH is low. In collecting tubules, PRCP deficiency could result in impaired AngII degradation. Increased AngII at this nephron site stimulates Na reabsorption and increases BP.
Databáze: MEDLINE
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