Kidney Transplantation in a Patient Lacking Cytosolic Phospholipase A 2 Proves Renal Origins of Urinary PGI-M and TX-M.

Autor:	Mitchell JA; From the National Heart and Lung Institute, Imperial College London, United Kingdom (J.A.M., N.S.K., D.M.R.); Blizard Institute, Queen Mary University of London, United Kingdom (R.B.K., W.E.W., M.V.C., M.M.Y., T.D.W.); National Institute for Environmental Health Sciences, Research Triangle, NC (M.L.E., D.C.Z.); Department of Nephrology (W.E.W., M.M.Y.) and Immunology Department (H.L.), Barts Health NHS Trust, London, United Kingdom; and Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN (G.L.M.)., Knowles RB; From the National Heart and Lung Institute, Imperial College London, United Kingdom (J.A.M., N.S.K., D.M.R.); Blizard Institute, Queen Mary University of London, United Kingdom (R.B.K., W.E.W., M.V.C., M.M.Y., T.D.W.); National Institute for Environmental Health Sciences, Research Triangle, NC (M.L.E., D.C.Z.); Department of Nephrology (W.E.W., M.M.Y.) and Immunology Department (H.L.), Barts Health NHS Trust, London, United Kingdom; and Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN (G.L.M.)., Kirkby NS; From the National Heart and Lung Institute, Imperial College London, United Kingdom (J.A.M., N.S.K., D.M.R.); Blizard Institute, Queen Mary University of London, United Kingdom (R.B.K., W.E.W., M.V.C., M.M.Y., T.D.W.); National Institute for Environmental Health Sciences, Research Triangle, NC (M.L.E., D.C.Z.); Department of Nephrology (W.E.W., M.M.Y.) and Immunology Department (H.L.), Barts Health NHS Trust, London, United Kingdom; and Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN (G.L.M.)., Reed DM; From the National Heart and Lung Institute, Imperial College London, United Kingdom (J.A.M., N.S.K., D.M.R.); Blizard Institute, Queen Mary University of London, United Kingdom (R.B.K., W.E.W., M.V.C., M.M.Y., T.D.W.); National Institute for Environmental Health Sciences, Research Triangle, NC (M.L.E., D.C.Z.); Department of Nephrology (W.E.W., M.M.Y.) and Immunology Department (H.L.), Barts Health NHS Trust, London, United Kingdom; and Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN (G.L.M.)., Edin ML; From the National Heart and Lung Institute, Imperial College London, United Kingdom (J.A.M., N.S.K., D.M.R.); Blizard Institute, Queen Mary University of London, United Kingdom (R.B.K., W.E.W., M.V.C., M.M.Y., T.D.W.); National Institute for Environmental Health Sciences, Research Triangle, NC (M.L.E., D.C.Z.); Department of Nephrology (W.E.W., M.M.Y.) and Immunology Department (H.L.), Barts Health NHS Trust, London, United Kingdom; and Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN (G.L.M.)., White WE; From the National Heart and Lung Institute, Imperial College London, United Kingdom (J.A.M., N.S.K., D.M.R.); Blizard Institute, Queen Mary University of London, United Kingdom (R.B.K., W.E.W., M.V.C., M.M.Y., T.D.W.); National Institute for Environmental Health Sciences, Research Triangle, NC (M.L.E., D.C.Z.); Department of Nephrology (W.E.W., M.M.Y.) and Immunology Department (H.L.), Barts Health NHS Trust, London, United Kingdom; and Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN (G.L.M.)., Chan MV; From the National Heart and Lung Institute, Imperial College London, United Kingdom (J.A.M., N.S.K., D.M.R.); Blizard Institute, Queen Mary University of London, United Kingdom (R.B.K., W.E.W., M.V.C., M.M.Y., T.D.W.); National Institute for Environmental Health Sciences, Research Triangle, NC (M.L.E., D.C.Z.); Department of Nephrology (W.E.W., M.M.Y.) and Immunology Department (H.L.), Barts Health NHS Trust, London, United Kingdom; and Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN (G.L.M.)., Longhurst H; From the National Heart and Lung Institute, Imperial College London, United Kingdom (J.A.M., N.S.K., D.M.R.); Blizard Institute, Queen Mary University of London, United Kingdom (R.B.K., W.E.W., M.V.C., M.M.Y., T.D.W.); National Institute for Environmental Health Sciences, Research Triangle, NC (M.L.E., D.C.Z.); Department of Nephrology (W.E.W., M.M.Y.) and Immunology Department (H.L.), Barts Health NHS Trust, London, United Kingdom; and Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN (G.L.M.)., Yaqoob MM; From the National Heart and Lung Institute, Imperial College London, United Kingdom (J.A.M., N.S.K., D.M.R.); Blizard Institute, Queen Mary University of London, United Kingdom (R.B.K., W.E.W., M.V.C., M.M.Y., T.D.W.); National Institute for Environmental Health Sciences, Research Triangle, NC (M.L.E., D.C.Z.); Department of Nephrology (W.E.W., M.M.Y.) and Immunology Department (H.L.), Barts Health NHS Trust, London, United Kingdom; and Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN (G.L.M.)., Milne GL; From the National Heart and Lung Institute, Imperial College London, United Kingdom (J.A.M., N.S.K., D.M.R.); Blizard Institute, Queen Mary University of London, United Kingdom (R.B.K., W.E.W., M.V.C., M.M.Y., T.D.W.); National Institute for Environmental Health Sciences, Research Triangle, NC (M.L.E., D.C.Z.); Department of Nephrology (W.E.W., M.M.Y.) and Immunology Department (H.L.), Barts Health NHS Trust, London, United Kingdom; and Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN (G.L.M.)., Zeldin DC; From the National Heart and Lung Institute, Imperial College London, United Kingdom (J.A.M., N.S.K., D.M.R.); Blizard Institute, Queen Mary University of London, United Kingdom (R.B.K., W.E.W., M.V.C., M.M.Y., T.D.W.); National Institute for Environmental Health Sciences, Research Triangle, NC (M.L.E., D.C.Z.); Department of Nephrology (W.E.W., M.M.Y.) and Immunology Department (H.L.), Barts Health NHS Trust, London, United Kingdom; and Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN (G.L.M.)., Warner TD; From the National Heart and Lung Institute, Imperial College London, United Kingdom (J.A.M., N.S.K., D.M.R.); Blizard Institute, Queen Mary University of London, United Kingdom (R.B.K., W.E.W., M.V.C., M.M.Y., T.D.W.); National Institute for Environmental Health Sciences, Research Triangle, NC (M.L.E., D.C.Z.); Department of Nephrology (W.E.W., M.M.Y.) and Immunology Department (H.L.), Barts Health NHS Trust, London, United Kingdom; and Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN (G.L.M.). t.d.warner@qmul.ac.uk j.a.mitchell@ic.ac.uk.
Jazyk:	angličtina
Zdroj:	Circulation research [Circ Res] 2018 Feb 16; Vol. 122 (4), pp. 555-559. Date of Electronic Publication: 2018 Jan 03.
DOI:	10.1161/CIRCRESAHA.117.312144
Abstrakt:	Rationale: The balance between vascular prostacyclin, which is antithrombotic, and platelet thromboxane A 2 , which is prothrombotic, is fundamental to cardiovascular health. Prostacyclin and thromboxane A 2 are formed after the concerted actions of cPLA 2 α (cytosolic phospholipase A 2 ) and COX (cyclooxygenase). Urinary 2,3-dinor-6-keto-PGF 1α (PGI-M) and 11-dehydro-TXB 2 (TX-M) have been taken as biomarkers of prostacyclin and thromboxane A 2 formation within the circulation and used to explain COX biology and patient phenotypes, despite concerns that urinary PGI-M and TX-M originate in the kidney. Objective: We report data from a remarkable patient carrying an extremely rare genetic mutation in cPLA 2 α, causing almost complete loss of prostacyclin and thromboxane A 2 , who was transplanted with a normal kidney resulting in an experimental scenario of whole-body cPLA 2 α knockout, kidney-specific knockin. By studying this patient, we can determine definitively the contribution of the kidney to the productions of PGI-M and TX-M and test their validity as markers of prostacyclin and thromboxane A 2 in the circulation. Methods and Results: Metabolites were measured using liquid chromatography-tandem mass spectrometry. Endothelial cells were grown from blood progenitors. Before kidney transplantation, the patient's endothelial cells and platelets released negligible levels of prostacyclin (measured as 6-keto-prostaglandin F 1α ) and thromboxane A 2 (measured as TXB 2 ), respectively. Likewise, the urinary levels of PGI-M and TX-M were very low. After transplantation and the establishment of normal renal function, the levels of PGI-M and TX-M in the patient's urine rose to within normal ranges, whereas endothelial production of prostacyclin and platelet production of thromboxane A 2 remained negligible. Conclusions: These data show that PGI-M and TX-M can be derived exclusively from the kidney without contribution from prostacyclin made by endothelial cells or thromboxane A 2 by platelets in the general circulation. Previous work relying on urinary metabolites of prostacyclin and thromboxane A 2 as markers of whole-body endothelial and platelet function now requires reevaluation. (© 2018 The Authors.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu