Identification of an Altered Matrix Signature in Kidney Aging and Disease
Van Agtmael, Tom
Norman, Jill T.
Long, David A.
Humphries, Martin J.
Miner, Jeffrey H.
AffiliationThe University of Manchester; University College London; Washington University; Manchester Royal Infirmary; University of Oxford; Oxford Brookes University; University of Glasgow; Royal Manchester Children’s Hospital; University of Chester
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AbstractBackground: 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. Although histologic and ultrastructural patterns of excess matrix form the basis of human disease classifications, a 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, and 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.
CitationMichael J. Randles, M. J., Lausecker, F., Kong, Q., Suleiman, H., Reid, G., Kolatsi-Joannou, M., Davenport, B., Tian, P., Falcone, S., Potter, P., Van Agtmael, T., Norman, J. T., Long, D. A., Humphries, M. J., Miner, J. H., & Lennon, R. (2021). Identification of an altered matrix signature in kidney aging and disease. Journal of the American Society of Nephrology, 32(7), 1713-1732. https://doi.org/10.1681/ASN.2020101442
PublisherAmerican Society of Nephrology
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