Mfsd2a-mediated lysolipid transport is important for renal recovery after acute kidney injury
Acute kidney injury (AKI) is a global public health concern with high mortality and morbidity. In ischemic–reperfusion injury (IRI), a main cause of AKI, the brush border membrane of S3 proximal tubules (PT) is lost to the tubular lumen. How injured tubules reconstitute lost membrane lipids during r...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-08-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227523000895 |
| _version_ | 1797737352284602368 |
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| author | Randy Y.J. Loke Cheen Fei Chin Gao Liang Bernice H. Wong Dwight L.A. Galam Bryan C. Tan Geok-Lin Chua Shintaro Minegishi Norihiko Morisawa Iulia Sidorov Bram Heijs Jens Titze Markus R. Wenk Federico Torta David L. Silver |
| author_facet | Randy Y.J. Loke Cheen Fei Chin Gao Liang Bernice H. Wong Dwight L.A. Galam Bryan C. Tan Geok-Lin Chua Shintaro Minegishi Norihiko Morisawa Iulia Sidorov Bram Heijs Jens Titze Markus R. Wenk Federico Torta David L. Silver |
| author_sort | Randy Y.J. Loke |
| collection | DOAJ |
| description | Acute kidney injury (AKI) is a global public health concern with high mortality and morbidity. In ischemic–reperfusion injury (IRI), a main cause of AKI, the brush border membrane of S3 proximal tubules (PT) is lost to the tubular lumen. How injured tubules reconstitute lost membrane lipids during renal recovery is not known. Here, we identified Mfsd2a, a sodium-dependent lysophosphatidylcholine (LPC) transporter, to be expressed specifically in the basolateral membrane of S3 PT. Using an in vivo activity probe for Mfsd2a, transport activity was found to be specific to the S3 PT. Mice with haploinsufficiency of Mfsd2a exhibited delayed recovery of renal function after acute IRI, with depressed urine osmolality and elevated levels of histological markers of damage, fibrosis, and inflammation, findings corroborated by transcriptomic analysis. Lipidomics revealed a deficiency in docosahexaenoic acid (DHA) containing phospholipids in Mfsd2a haploinsufficiency. Treatment of Mfsd2a haploinsufficient mice with LPC-DHA improved renal function and reduced markers of injury, fibrosis, and inflammation. Additionally, LPC-DHA treatment restored S3 brush border membrane architecture and normalized DHA-containing phospholipid content. These findings indicate that Mfsd2a-mediated transport of LPC-DHA is limiting for renal recovery after AKI and suggest that LPC-DHA could be a promising dietary supplement for improving recovery following AKI. |
| first_indexed | 2024-03-12T13:27:26Z |
| format | Article |
| id | doaj.art-672d13e383c743709655a740077d87eb |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-03-12T13:27:26Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-672d13e383c743709655a740077d87eb2023-08-25T04:23:33ZengElsevierJournal of Lipid Research0022-22752023-08-01648100416Mfsd2a-mediated lysolipid transport is important for renal recovery after acute kidney injuryRandy Y.J. Loke0Cheen Fei Chin1Gao Liang2Bernice H. Wong3Dwight L.A. Galam4Bryan C. Tan5Geok-Lin Chua6Shintaro Minegishi7Norihiko Morisawa8Iulia Sidorov9Bram Heijs10Jens Titze11Markus R. Wenk12Federico Torta13David L. Silver14Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, SingaporeSignature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, SingaporeSingapore Lipidomics Incubator, Life Sciences Institute, NUS, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, NUS, SingaporeSignature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, SingaporeSignature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, SingaporeSignature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, SingaporeSignature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, SingaporeSignature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, SingaporeSignature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, SingaporeCenter of Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands; The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, the NetherlandsCenter of Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands; The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, the NetherlandsSignature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, SingaporeSingapore Lipidomics Incubator, Life Sciences Institute, NUS, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, NUS, SingaporeSingapore Lipidomics Incubator, Life Sciences Institute, NUS, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, NUS, SingaporeSignature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore; For correspondence: David L. SilverAcute kidney injury (AKI) is a global public health concern with high mortality and morbidity. In ischemic–reperfusion injury (IRI), a main cause of AKI, the brush border membrane of S3 proximal tubules (PT) is lost to the tubular lumen. How injured tubules reconstitute lost membrane lipids during renal recovery is not known. Here, we identified Mfsd2a, a sodium-dependent lysophosphatidylcholine (LPC) transporter, to be expressed specifically in the basolateral membrane of S3 PT. Using an in vivo activity probe for Mfsd2a, transport activity was found to be specific to the S3 PT. Mice with haploinsufficiency of Mfsd2a exhibited delayed recovery of renal function after acute IRI, with depressed urine osmolality and elevated levels of histological markers of damage, fibrosis, and inflammation, findings corroborated by transcriptomic analysis. Lipidomics revealed a deficiency in docosahexaenoic acid (DHA) containing phospholipids in Mfsd2a haploinsufficiency. Treatment of Mfsd2a haploinsufficient mice with LPC-DHA improved renal function and reduced markers of injury, fibrosis, and inflammation. Additionally, LPC-DHA treatment restored S3 brush border membrane architecture and normalized DHA-containing phospholipid content. These findings indicate that Mfsd2a-mediated transport of LPC-DHA is limiting for renal recovery after AKI and suggest that LPC-DHA could be a promising dietary supplement for improving recovery following AKI.http://www.sciencedirect.com/science/article/pii/S0022227523000895Acute kidney injuryPhospholipidTransporterMfsd2aomega-3 fatty acidDHA |
| spellingShingle | Randy Y.J. Loke Cheen Fei Chin Gao Liang Bernice H. Wong Dwight L.A. Galam Bryan C. Tan Geok-Lin Chua Shintaro Minegishi Norihiko Morisawa Iulia Sidorov Bram Heijs Jens Titze Markus R. Wenk Federico Torta David L. Silver Mfsd2a-mediated lysolipid transport is important for renal recovery after acute kidney injury Journal of Lipid Research Acute kidney injury Phospholipid Transporter Mfsd2a omega-3 fatty acid DHA |
| title | Mfsd2a-mediated lysolipid transport is important for renal recovery after acute kidney injury |
| title_full | Mfsd2a-mediated lysolipid transport is important for renal recovery after acute kidney injury |
| title_fullStr | Mfsd2a-mediated lysolipid transport is important for renal recovery after acute kidney injury |
| title_full_unstemmed | Mfsd2a-mediated lysolipid transport is important for renal recovery after acute kidney injury |
| title_short | Mfsd2a-mediated lysolipid transport is important for renal recovery after acute kidney injury |
| title_sort | mfsd2a mediated lysolipid transport is important for renal recovery after acute kidney injury |
| topic | Acute kidney injury Phospholipid Transporter Mfsd2a omega-3 fatty acid DHA |
| url | http://www.sciencedirect.com/science/article/pii/S0022227523000895 |
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