Identification of an altered matrix signature in kidney ageing and disease

Background: Accumulation of extracellular matrix in organs and tissues is a feature of both ageing and disease. In the kidney, glomerulosclerosis and tubulointerstitial fibrosis accompany the decline in organ function, which is irretrievable with current therapies leading to inevitable kidney failure. Whilst histological and ultrastructural patterns of excess matrix form the basis of human disease classifications, the 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 ageing and to existing kidney disease datasets to identify common molecular features. Results: We found that ultrastructural changes in basement membranes are associated with altered cell adhesion and metabolic processes and with distinct matrix proteomes during ageing and kidney disease progression in mice. Within the altered matrix, we observed a reduction in basement membrane components (laminins, type IV collagen, type XVIII collagen) and a corresponding increase in interstitial matrix proteins (collagens I, III, VI, XV, fibrinogens and nephronectin)
and this pattern was also seen in human kidney ageing. 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 ageing and disease and identifies a common signature of proteins that provides insight into mechanisms of response to kidney injury and repair.