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SARS-CoV-2 infection causes a decline in renal megalin expression and affects vitamin D metabolism in the kidney of K18-hACE2 mice

Kurosaki et al., Scientific Reports, doi:10.1038/s41598-024-75338-9
Oct 2024  
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Vitamin D for COVID-19
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Mouse study showing that SARS-CoV-2 infection decreases renal megalin expression and affects vitamin D metabolism in K18-hACE2 mice. Authors found that infected mice experienced acute kidney injury, suppressed megalin protein levels in proximal tubules, decreased vitamin D receptor localization in the nucleus, and increased mRNA expression of vitamin D-related genes CYP27B1 and CYP24A1. Serum vitamin D levels were unchanged, but an increase in pro-inflammatory TNF-alpha and decrease in anti-inflammatory IL-4 were observed in kidneys of infected mice. The findings suggest megalin loss may impact the local immunomodulatory role of vitamin D in the kidney during SARS-CoV-2 infection.
21 preclinical studies support the efficacy of vitamin D for COVID-19:
Vitamin D has been identified by the European Food Safety Authority (EFSA) as having sufficient evidence for a causal relationship between intake and optimal immune system function20-23. Vitamin D inhibits SARS-CoV-2 replication in vitro10,17, mitigates lung inflammation, damage, and lethality in mice with an MHV-3 model for β-CoV respiratory infections10,17, reduces SARS-CoV-2 replication in nasal epithelial cells via increased type I interferon expression13, downregulates proinflammatory cytokines IL-1β and TNF-α in SARS-CoV-2 spike protein-stimulated cells9, attenuates nucleocapsid protein-induced hyperinflammation by inactivating the NLRP3 inflammasome through the VDR-BRCC3 signaling pathway14, may be neuroprotective by protecting the blood-brain barrier, reducing neuroinflammation, and via immunomodulatory effects24, minimizes platelet aggregation mediated by SARS-CoV-2 spike protein via inhibiting integrin αIIbβ3 outside-in signaling8, and improves regulatory immune cell levels and control of proinflammatory cytokines in severe COVID-1925. Symptomatic COVID-19 is associated with a lower frequency of natural killer (NK) cells and vitamin D has been shown to improve NK cell activity26,27.
Kurosaki et al., 16 Oct 2024, peer-reviewed, 12 authors. Contact: kuboma@kitasato-u.ac.jp.
This PaperVitamin DAll
SARS-CoV-2 infection causes a decline in renal megalin expression and affects vitamin D metabolism in the kidney of K18-hACE2 mice
Yoshifumi Kurosaki, Toshihide Matsumoto, Takayuki Uematsu, Fumitaka Kawakami, Rei Kawashima, Shun Tamaki, Motoki Imai, Takafumi Ichikawa, Naohito Ishii, Hidero Kitasato, Hideaki Hanaki, Makoto Kubo
Scientific Reports, doi:10.1038/s41598-024-75338-9
Patients with coronavirus disease 2019 (COVID-19) often experience acute kidney injury, linked to disease severity or mortality, along with renal tubular dysfunction and megalin loss in proximal tubules. Megalin plays a crucial role in kidney vitamin D metabolism. However, the impact of megalin loss on vitamin D metabolism during COVID-19 is unclear. This study investigated whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection reduces megalin expression in proximal tubules and its subsequent effect on vitamin D metabolism in mice expressing human angiotensin converting enzyme 2 (K18-hACE2 mice). Histological and immunohistochemical staining analyses revealed glomerular and capillary congestion, and elevated renal neutrophil gelatinase-associated lipocalin levels, indicative of acute kidney injury in K18-hACE2 mice. In SARS-CoV-2-infected mice, immunohistochemical staining revealed suppressed megalin protein levels. Decreased vitamin D receptor (VDR) localization in the nucleus and increased mRNA expression of VDR, CYP27B1, and CYP24A1 were observed by quantitative PCR in SARS-CoV-2-infected mice. Serum vitamin D levels remained similar in infected and vehicle-treated mice, but an increase in tumor necrosis factor-alpha and a decrease in IL-4 mRNA expression were observed in the kidneys of the SARS-CoV-2 group. These findings suggest that megalin loss in SARS-CoV-2 infection may impact the local role of vitamin D in kidney immunomodulation, even when blood vitamin D levels remain unchanged. Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic. Studies have reported a correlation between acute kidney injury (AKI) and overall disease severity or mortality 1,2 . A systematic review and meta-analysis of 20 cohorts with COVID-19-associated AKI (CoV-AKI) reported a prevalence of AKI ranging from 0.5 to 80% (with an average of 17%) and 77% of the patients with AKI exhibited severe COVID-19 manifestation 3 . Some mechanisms for kidney injury in COVID-19 have been proposed, including direct infection, inflammatory injury followed by a cytokine storm, and ischemic injury caused by multiorgan failure 4,5 ; however, the cause of kidney injury in COVID-19 remains unclear. Previous studies have reported that acute tubular injury is the main finding in patients with CoV-AKI [6] [7] [8] . A postmortem study patients revealed significant acute tubular injury in all patients 9 . Low-grade proteinuria has been detected in patients with COVID-19 without AKI 10, 11 . Proteinuria during hospitalization was significantly associated with an increased risk of death 12 , which suggests that renal tubular dysfunction
Author contributions Y.K., H.K., H.H., and M.K. provided conception and design of research; Y.K., T.M., T.U., and M.I. performed experiments; Y.K., T.M., F.K., R.K., and S.T. analyzed data; Y.K., T.U., F.K., R.K., T.I., N.I., H.K., H.H., and M.K. interpreted results of experiments; Y.K. and T.M. prepared figures; Y.K. drafted manuscript; Y.K., T.U., T.I., N.I., H.K., H.H., and M.K. edited and revised manuscript; Y.K., T.M., T.U., F.K., R.K., S.T., M.I., T.I., N.I., H.K., H.H., and M.K. approved final version of manuscript. Competing interests The authors declare no competing interests. Additional information Supplementary Information The online version contains supplementary material available at https://doi. org/10.1038/s41598-024-75338-9 . Correspondence and requests for materials should be addressed to M.K. Reprints and permissions information is available at www.nature.com/reprints. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence..
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Vitamin D and acute ' 'kidney injury: A two-way causality relation and a predictive, ' 'prognostic, and therapeutic role of vitamin D. Front Nutr. 7, 630951 ' '(2020).', 'journal-title': 'Front Nutr.'}, { 'key': '75338_CR24', 'doi-asserted-by': 'publisher', 'first-page': '158', 'DOI': '10.1016/j.semnephrol.2012.12.016', 'volume': '33', 'author': 'C Bosworth', 'year': '2013', 'unstructured': 'Bosworth, C. & de Boer, I. H. Impaired vitamin D metabolism in CKD. ' 'Semin. Nephrol. 33, 158–168 (2013).', 'journal-title': 'Semin. Nephrol.'}, { 'key': '75338_CR25', 'doi-asserted-by': 'publisher', 'first-page': '13895', 'DOI': '10.1073/pnas.241516998', 'volume': '98', 'author': 'A Nykjaer', 'year': '2001', 'unstructured': 'Nykjaer, A. et al. Cubilin dysfunction causes abnormal metabolism of the ' 'steroid hormone 25(OH) vitamin D(3). Proc. Natl. Acad. Sci. USA 98, ' '13895–13900 (2001).', 'journal-title': 'Proc. Natl. Acad. Sci. USA'}, { 'key': '75338_CR26', 'doi-asserted-by': 'publisher', 'first-page': '9725', 'DOI': '10.1073/pnas.91.21.9725', 'volume': '91', 'author': 'A Saito', 'year': '1994', 'unstructured': 'Saito, A., Pietromonaco, S., Loo, A. K. & Farquhar, M. G. Complete ' 'cloning and sequencing of rat gp330/"megalin," a distinctive member of ' 'the low density lipoprotein receptor gene family. Proc. Natl. Acad. Sci. ' 'USA 91, 9725–9729 (1994).', 'journal-title': 'Proc. Natl. Acad. Sci. USA'}, { 'key': '75338_CR27', 'doi-asserted-by': 'publisher', 'first-page': '132', 'DOI': '10.1111/j.1432-1033.1996.0132u.x', 'volume': '239', 'author': 'G Hjalm', 'year': '1996', 'unstructured': 'Hjalm, G. et al. Cloning and sequencing of human gp330, a Ca(2+)-binding ' 'receptor with potential intracellular signaling properties. Eur. J. ' 'Biochem. 239, 132–137 (1996).', 'journal-title': 'Eur. J. Biochem.'}, { 'key': '75338_CR28', 'doi-asserted-by': 'publisher', 'first-page': '507', 'DOI': '10.1016/S0092-8674(00)80655-8', 'volume': '96', 'author': 'A Nykjaer', 'year': '1999', 'unstructured': 'Nykjaer, A. et al. An endocytic pathway essential for renal uptake and ' 'activation of the steroid 25-(OH) vitamin D3. Cell 96, 507–515 (1999).', 'journal-title': 'Cell'}, { 'key': '75338_CR29', 'doi-asserted-by': 'publisher', 'first-page': '1296', 'DOI': '10.1016/j.kint.2020.07.019', 'volume': '98', 'author': 'A Werion', 'year': '2020', 'unstructured': 'Werion, A. et al. SARS-CoV-2 causes a specific dysfunction of the kidney ' 'proximal tubule. Kidney Int. 98, 1296–1307 (2020).', 'journal-title': 'Kidney Int.'}, { 'key': '75338_CR30', 'doi-asserted-by': 'publisher', 'first-page': '2242', 'DOI': '10.1681/ASN.2020111546', 'volume': '32', 'author': 'D Omer', 'year': '2021', 'unstructured': 'Omer, D. et al. 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Nephrol.'}, { 'key': '75338_CR37', 'doi-asserted-by': 'publisher', 'first-page': '270', 'DOI': '10.1038/s41586-020-2012-7', 'volume': '579', 'author': 'P Zhou', 'year': '2020', 'unstructured': 'Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus ' 'of probable bat origin. Nature 579, 270–273 (2020).', 'journal-title': 'Nature'}, { 'key': '75338_CR38', 'doi-asserted-by': 'publisher', 'first-page': '74', 'DOI': '10.5527/wjn.v4.i1.74', 'volume': '4', 'author': 'S Mizuiri', 'year': '2015', 'unstructured': 'Mizuiri, S. & Ohashi, Y. ACE and ACE2 in kidney disease. World J. ' 'Nephrol. 4, 74–82 (2015).', 'journal-title': 'World J. Nephrol.'}, { 'key': '75338_CR39', 'doi-asserted-by': 'publisher', 'first-page': '924', 'DOI': '10.34067/KID.0002172021', 'volume': '2', 'author': 'S George', 'year': '2021', 'unstructured': 'George, S. et al. Evidence for SARS-CoV-2 Spike Protein in the Urine of ' 'COVID-19 Patients. 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The link between vitamin D status and ' 'NF-kappaB-associated renal dysfunction in experimental diabetes ' 'mellitus. Biochim. Biophys. Acta Gen. Subj. 1866, 130136 (2022).', 'journal-title': 'Biochim. Biophys. Acta Gen. Subj.'}, { 'key': '75338_CR52', 'doi-asserted-by': 'publisher', 'first-page': '1343', 'DOI': '10.1038/ki.2008.453', 'volume': '74', 'author': 'D Zehnder', 'year': '2008', 'unstructured': 'Zehnder, D. et al. Reduction of the vitamin D hormonal system in kidney ' 'disease is associated with increased renal inflammation. Kidney Int. 74, ' '1343–1353 (2008).', 'journal-title': 'Kidney Int.'}, { 'key': '75338_CR53', 'doi-asserted-by': 'publisher', 'first-page': '2754', 'DOI': '10.1093/jn/136.11.2754', 'volume': '136', 'author': 'MJ Rowling', 'year': '2006', 'unstructured': 'Rowling, M. J., Kemmis, C. M., Taffany, D. A. & Welsh, J. ' 'Megalin-mediated endocytosis of vitamin D binding protein correlates ' 'with 25-hydroxycholecalciferol actions in human mammary cells. J. 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