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Increased urinary lysophosphatidic acid in mouse with subtotal nephrectomy: potential involvement in chronic kidney disease

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Abstract

Increased incidence of chronic kidney disease (CKD) with consecutive progression to end-stage renal disease represents a significant burden to healthcare systems. Renal tubulointerstitial fibrosis (TIF) is a classical hallmark of CKD and is well correlated with the loss of renal function. The bioactive lysophospholipid lysophosphatidic acid (LPA), acting through specific G-protein-coupled receptors, was previously shown to be involved in TIF development in a mouse model of unilateral ureteral obstruction. Here, we study the role of LPA in a mouse subjected to subtotal nephrectomy (SNx), a more chronic and progressive model of CKD. Five months after surgical nephron reduction, SNx mice showed massive albuminuria, extensive TIF, and glomerular hypertrophy when compared to sham-operated animals. Urinary and plasma levels of LPA were analyzed using liquid chromatography tandem mass spectrometry. LPA was significantly increased in SNx urine, not in plasma, and was significantly correlated with albuminuria and TIF. Moreover, SNx mice showed significant downregulation in the renal expression of lipid phosphate phosphohydrolases (LPP1, 2, and 3) that might be involved in reduced LPA bioavailability through dephosphorylation. We concluded that SNx increases urinary LPA through a mechanism that could involve co-excretion of plasma LPA with albumin associated with a reduction of its catabolism in the kidney. Because of the previously demonstrated profibrotic activity of LPA, the association of urinary LPA with TIF suggests the potential involvement of LPA in the development of advanced CKD in the SNx mouse model. Targeting LPA metabolism might represent an interesting approach in CKD treatment.

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Acknowledgments

This work was supported by grants from INSERM and the Société Francophone du Diabète (grant 2015). We thank Christine Delage and Denis Calise (INSERM US06 CREFRE, Toulouse, France) for SNx surgery. Koryun Mirzoyan is supported by a Ph.D. grant from Europe (ERASMUS MUNDUS, MEDEA). All authors participated in the conception and design, or analysis and interpretation of the data, contributed to drafting and revising the manuscript, and gave final approval of the version to be published.

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Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France

    Koryun Mirzoyan, Anna Baïotto, Aude Dupuy, Dimitri Marsal, Colette Denis, Claire Vinel, Pierre Sicard, Justine Bertrand-Michel, Joost P. Schanstra, Julie Klein & Jean-Sébastien Saulnier-Blache

  2. Université Toulouse III Paul-Sabatier Toulouse, Toulouse, France

    Koryun Mirzoyan, Anna Baïotto, Aude Dupuy, Dimitri Marsal, Colette Denis, Claire Vinel, Pierre Sicard, Justine Bertrand-Michel, Joost P. Schanstra, Julie Klein & Jean-Sébastien Saulnier-Blache

  3. Lipidomic Core Facility, Metatoul Platform, Université de Toulouse, Université Paul Sabatier, Toulouse, France

    Aude Dupuy & Justine Bertrand-Michel

  4. DéTROI - Inserm U1188 - Université de La Réunion, Sainte Clotilde, France

    Jean-Loup Bascands

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  1. Koryun Mirzoyan
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  2. Anna Baïotto
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  12. Jean-Sébastien Saulnier-Blache
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Corresponding author

Correspondence to Jean-Sébastien Saulnier-Blache.

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All experiments were conducted in accordance with National Institute of Health guidelines for the care and use of laboratory animals and were approved by a local ethics committee (CEEA#122).

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Mirzoyan, K., Baïotto, A., Dupuy, A. et al. Increased urinary lysophosphatidic acid in mouse with subtotal nephrectomy: potential involvement in chronic kidney disease. J Physiol Biochem 72, 803–812 (2016). https://doi.org/10.1007/s13105-016-0518-0

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  • DOI: https://doi.org/10.1007/s13105-016-0518-0

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