Kidney derived apolipoprotein M and its role in acute kidney injury

Line S Bisgaard; Pernille M Christensen; Jeongah Oh; Federico Torta; Ernst-Martin Füchtbauer; Lars Bo Nielsen; Christina Christoffersen

doi:10.3389/fphar.2024.1328259

Kidney derived apolipoprotein M and its role in acute kidney injury

Front Pharmacol. 2024 Jan 19:15:1328259. doi: 10.3389/fphar.2024.1328259. eCollection 2024.

Authors

Line S Bisgaard^{1

2}, Pernille M Christensen^{1

2}, Jeongah Oh³, Federico Torta^{3

4}, Ernst-Martin Füchtbauer⁴, Lars Bo Nielsen⁵, Christina Christoffersen^{1

2}

Affiliations

¹ Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.
² Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
³ Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore, Singapore.
⁴ Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
⁵ The Faculty of Health Sciences, Aarhus University, Aarhus, Denmark.

Abstract

Aim: Apolipoprotein M (apoM) is mainly expressed in liver and in proximal tubular epithelial cells in the kidney. In plasma, apoM associates with HDL particles via a retained signal peptide and carries sphingosine-1-phosphate (S1P), a small bioactive lipid. ApoM is undetectable in urine from healthy individuals but lack of megalin receptors in proximal tubuli cells induces loss of apoM into the urine. Besides this, very little is known about kidney-derived apoM. The aim of this study was to address the role of apoM in kidney biology and in acute kidney injury. Methods: A novel kidney-specific human apoM transgenic mouse model (RPTEC-hapoM^TG) was generated and subjected to either cisplatin or ischemia/reperfusion injury. Further, a stable transfection of HK-2 cells overexpressing human apoM (HK-2-hapoM^TG) was developed to study the pattern of apoM secretion in proximal tubuli cells. Results: Human apoM was present in plasma from RPTEC-hapoM^TG mice (mean 0.18 μM), with a significant increase in plasma S1P levels. In vitro apoM was secreted to both the apical (urine) and basolateral (blood) compartment from proximal tubular epithelial cells. However, no differences in kidney injury score was seen between RPTEC-hapoM^TG and wild type (WT) mice upon kidney injury. Further, gene expression of inflammatory markers (i.e., IL6, MCP-1) was similar upon ischemia/reperfusion injury. Conclusion: Our study suggests that kidney-derived apoM is secreted to plasma, supporting a role for apoM in sequestering molecules from excretion in urine. However, overexpression of human apoM in the kidney did not protect against acute kidney injury.

Keywords: HK-2 cell; acute kidney injury (AKI); apolipoprotein; apolipoprotein M; cell culture; kidney; transwell.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by research grants from the Faculty of Health and Medical Sciences, University of Copenhagen, the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation, grant number NNF17SA0031406, the Novo Nordisk foundation, Augustinus Fonden, and a travel grant from Knud Højgaards Fond.