Michael Randles1, Franziska Lausecker2, Qing Kong3, Hani Suleiman4, Graeme Reid5, Maria Kolatsi-Joannou6, Pinyuan Tian7, Sara Falcone8, Bernard Davenport9, Paul Potter10, Tom Van Agtmael11, Jill Norman12, David Long13, Martin Humphries14, Jeffrey Miner15, Rachel Lennon16. 1. M Randles, Wellcome Trust Centre for Cell-Matrix Research, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom of Great Britain and Northern Ireland. 2. F Lausecker, Wellcome Trust Centre for Cell-Matrix Research, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom of Great Britain and Northern Ireland. 3. Q Kong, Department of Renal Medicine, University College London, London, UK, London, United Kingdom of Great Britain and Northern Ireland. 4. H Suleiman, Renal Division, Washington University School of Medicine, St Louis, United States. 5. G Reid, Department of Histopathology, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom of Great Britain and Northern Ireland. 6. M Kolatsi-Joannou, Developmental Biology and Cancer Programme, UCL Great Ormond Institute of Child Health, London, United Kingdom of Great Britain and Northern Ireland. 7. P Tian, Wellcome Trust Centre for Cell-Matrix Research, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom of Great Britain and Northern Ireland. 8. S Falcone, Centre for Cellular and Molecular Physiology, University of Oxford, Oxford, United Kingdom of Great Britain and Northern Ireland. 9. B Davenport, Wellcome Trust Centre for Cell-Matrix Research, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom of Great Britain and Northern Ireland. 10. P Potter, Department Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, United Kingdom of Great Britain and Northern Ireland. 11. T Van Agtmael, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom of Great Britain and Northern Ireland. 12. J Norman, Department of Renal Medicine, University College London, London, United Kingdom of Great Britain and Northern Ireland. 13. D Long, Developmental Biology and Cancer Programme, UCL Great Ormond Institute of Child Health, London, United Kingdom of Great Britain and Northern Ireland. 14. M Humphries, Wellcome Trust Centre for Cell-Matrix Research, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom of Great Britain and Northern Ireland. 15. J Miner, Renal Division, Washington University School of Medicine, St Louis, United States. 16. R Lennon, Wellcome Trust Centre for Cell-Matrix Research, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, United Kingdom of Great Britain and Northern Ireland Rachel.Lennon@manchester.ac.uk.
Abstract
Background: Accumulation of extracellular matrix in organs and tissues is a feature of both aging and disease. In the kidney, glomerulosclerosis and tubulointerstitial fibrosis accompany the decline in function, which current therapies cannot address, leading to organ failure. Whilst histological and ultrastructural patterns of excess matrix form the basis of human disease classifications, comprehensive molecular resolution of abnormal matrix is lacking. Methods: Using mass spectrometry-based proteomics we resolved matrix composition over age in mouse models of kidney disease. We compared the changes in mice with a global characterization of human kidney matrix during aging and to existing kidney disease datasets to identify common molecular features. Results: Ultrastructural changes in basement membranes are associated with altered cell adhesion and metabolic processes and with distinct matrix proteomes during aging and kidney disease progression in mice. Within the altered matrix, basement membrane components (laminins, type IV collagen, type XVIII collagen) were reduced and interstitial matrix proteins (collagens I, III, VI, XV, fibrinogens and nephronectin) were increased, a pattern also seen in human kidney aging. Indeed, this signature of matrix proteins was consistently modulated across all age and disease comparisons and the increase in interstitial matrix was also observed in human kidney disease datasets. Conclusions: This study provides deep molecular resolution of matrix accumulation in kidney aging and disease and identifies a common signature of proteins that provides insight into mechanisms of response to kidney injury and repair.
Background: Accumulation of extracellular matrix in organs and tissues is a feature of both aging and disease. In the kidney, glomerulosclerosis and tubulointerstitial fibrosis accompany the decline in function, which current therapies cannot address, leading to organ failure. Whilst histological and ultrastructural patterns of excess matrix form the basis of human disease classifications, comprehensive molecular resolution of abnormal matrix is lacking. Methods: Using mass spectrometry-based proteomics we resolved matrix composition over age in mouse models of kidney disease. We compared the changes in mice with a global characterization of human kidney matrix during aging and to existing kidney disease datasets to identify common molecular features. Results: Ultrastructural changes in basement membranes are associated with altered cell adhesion and metabolic processes and with distinct matrix proteomes during aging and kidney disease progression in mice. Within the altered matrix, basement membrane components (laminins, type IV collagen, type XVIII collagen) were reduced and interstitial matrix proteins (collagens I, III, VI, XV, fibrinogens and nephronectin) were increased, a pattern also seen in human kidney aging. Indeed, this signature of matrix proteins was consistently modulated across all age and disease comparisons and the increase in interstitial matrix was also observed in human kidney disease datasets. Conclusions: This study provides deep molecular resolution of matrix accumulation in kidney aging and disease and identifies a common signature of proteins that provides insight into mechanisms of response to kidney injury and repair.
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