Details

Autor(en) / Beteiligte

• Mitchell, Jane A
• Knowles, Rebecca B
• Kirkby, Nicholas S
• Reed, Daniel M
• Edin, Matthew L
• White, William E
• Chan, Melissa V
• Longhurst, Hilary
• Yaqoob, Magdi M
• Milne, Ginger L
• Zeldin, Darryl C
• Warner, Timothy D

Titel

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

Ist Teil von

• Circulation research, 2018-02, Vol.122 (4), p.555-559

Ort / Verlag

United States

Erscheinungsjahr

2018

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• The balance between vascular prostacyclin, which is antithrombotic, and platelet thromboxane A , which is prothrombotic, is fundamental to cardiovascular health. Prostacyclin and thromboxane A are formed after the concerted actions of cPLA α (cytosolic phospholipase A ) and COX (cyclooxygenase). Urinary 2,3-dinor-6-keto-PGF (PGI-M) and 11-dehydro-TXB (TX-M) have been taken as biomarkers of prostacyclin and thromboxane A 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. We report data from a remarkable patient carrying an extremely rare genetic mutation in cPLA α, causing almost complete loss of prostacyclin and thromboxane A , who was transplanted with a normal kidney resulting in an experimental scenario of whole-body cPLA 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 in the circulation. 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 ) and thromboxane A (measured as TXB ), 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 remained negligible. 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 by platelets in the general circulation. Previous work relying on urinary metabolites of prostacyclin and thromboxane A as markers of whole-body endothelial and platelet function now requires reevaluation.