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

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Abstract

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.

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Acknowledgements

We thank Dr. Lisa Wilsbacher for careful review of the manuscript and providing expert opinion on studies on the cardiac phenotype.

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Authors and Affiliations

  1. Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Christoph Maier, Philipp K. Haber, Jan Wysocki, Minghao Ye & Daniel Batlle

  2. Charité—Universitätsmedizin Berlin, Berlin, Germany

    Christoph Maier, Philipp K. Haber & Michael Bader

  3. Max Delbrück Center for Molecular Medicine, Berlin, Germany

    Ines Schadock & Michael Bader

  4. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Yashpal Kanwar

  5. Department of Radiology, Case Western Reserve University, Cleveland, OH, USA

    Christopher A. Flask & Xin Yu

  6. Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA

    Christopher A. Flask & Xin Yu

  7. Department of Medicine, Division of Cardiology, University Hospitals Case Medical Center and Case Western Reserve University, Cleveland, OH, USA

    Brian D. Hoit

  8. Department of Medicine, Division of Hematology and Oncology, University Hospitals Case Medical Center and Case Western Reserve University, Cleveland, OH, USA

    Gregory N. Adams & Alvin H. Schmaier

  9. National Institute of Science and Technology in Nanobiopharmaceutics, Federal University of Minas Gerais, Belo Horizonte, Brazil

    Michael Bader

  10. German Center for Cardiovascular Research (DZHK), Berlin site, Berlin, Germany

    Michael Bader

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  1. Christoph Maier
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  2. Ines Schadock
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Correspondence to Daniel Batlle.

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Funding

D.B. had grant support for these studies from the National Institute of Diabetes and Digestive and Kidney Diseases (DK 080089) and the Reuben Feinberg Foundation. C.M. and P.K.H. received funding from the German Academic Exchange Service (DAAD). A.H.S. has support from the NIH NHLBI HL0527719, HL112666, HL109561, and DOD BC150596P1.

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The authors declare that they have no conflict of interest.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Maier, C., Schadock, I., Haber, P.K. et al. Prolylcarboxypeptidase deficiency is associated with increased blood pressure, glomerular lesions, and cardiac dysfunction independent of altered circulating and cardiac angiotensin II. J Mol Med 95, 473–486 (2017). https://doi.org/10.1007/s00109-017-1513-9

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