Randles, M. et al. (2021) Identification of an altered matrix signature in kidney aging and disease. Journal of the American Society of Nephrology, 32(7), pp. 1713-1732. (doi: 10.1681/ASN.2020101442) (PMID:34049963)
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Abstract
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. 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. 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. 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.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work was supported by Wellcome Trust Senior Fellowship Award 202860/Z/16/Z (to R. Lennon) and grant 092015 (to M.J. Humphries), Kidney Research UK https://doi.org/10.13039/501100000291 grant RP52/2014 (awarded to R. Lennon and J.H. Miner to support a postdoctoral research assistant position for M.J. Randles), and Cancer Research UK grant C13329. D.A. Long’s laboratory is supported by Medical Research Council grant MR/P018629/1; Diabetes UK grants 13/0004763, 15/0005283, and 17/0005733; Kidney Research UK grant RP36/2015; and by the NIHR Imperial Biomedical Research Centre at Great Ormond Street Hospital for Children University College London Hospitals NHS Foundation Trust. T. Van Agtmael’s laboratory is supported by Kidney Research UK grant RP 19/2012, British Heart Foundation grant PG/15/92/31813, and Medical Research Council grant MR/R005567-1. The authors also acknowledge Wellcome Trust core funding under grant 203128/Z/16/Z to the Wellcome Centre for Cell-Matrix Research at the University of Manchester. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Van Agtmael, Professor Tom |
| Authors: | Randles, M., Lausecker, F., Kong, Q., Suleiman, H., Reid, G., Kolatsi-Joannou, M., Tian, P., Falcone, S., Davenport, B., Potter, P., Van Agtmael, T., Norman, J., Long, D., Humphries, M., Miner, J., and Lennon, R. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
| Journal Name: | Journal of the American Society of Nephrology |
| Publisher: | American Society of Nephrology |
| ISSN: | 1046-6673 |
| ISSN (Online): | 1533-3450 |
| Published Online: | 30 June 2021 |
| Copyright Holders: | Copyright © 2021 by the American Society of Nephrology |
| First Published: | First published in Journal of the American Society of Nephrology 32(7):1713-1732 |
| Publisher Policy: | Reproduced in accordance with the publisher copyright policy |
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