Identification of an Altered Matrix Signature in Kidney Aging and Disease

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.

A basement membrane discovery pipeline uncovers network complexity, new regulators, and human disease associations

“…We discovered many genes that function to restrict BM collagen IV levels. These collagen IV limiting mechanisms might break down during senescence and disease, as altered collagen IV levels is a hallmark of aging, diabetes, and Alzheimer's disease 19,[64][65][66] . We found the TGFβ pathway and ROBO restrict collagen IV accumulation in C. elegans and zebrafish.…”

“…To investigate BM diversity in human tissues, the relative abundance of the BM zone network within proteomic datasets for human kidney 19 , liver 16 , colon 16 , and omentum 32 was ranked (Supplementary table 8). We found a common set of BM zone proteins that were abundant across all tissues, including COL4A1/2, COL6A1/A2/A3, LAMB2/C1, NID1, and HSPG2 (perlecan), and identified proteins with highly variable abundance, such as DCN and TINAG (Fig.…”

Molecular and Cellular Mechanisms Underlying the Initiation and Progression of Alport Glomerular Pathology

“…This may contribute to why ACE inhibitors, which reduce intraglomerular pressure, slow the progression of Alport kidney disease in both mice and human ( 9 – 11 ). A recent mass-spectroscopy-based proteomics study demonstrated aan overall reduction in basement membrane proteins in glomerular matrix from Alprot mice relative to wild type mice with an overall increase in interstitial matrix proteins ( 12 ). These changes are likely to contribute to the biomechanical prpoperties of the GBM in Alport syndrome.…”

Time-lapsed proteomics reveals a role for the novel protein, SNED1, in modulating ECM composition and protein folding

“…This method infers protein presence based on the identification of the most abundant peptides in any given sample. Proteomics has revealed that the ECM of any given tissue is made of well over 100 distinct proteins and has allowed the identification of ECM protein signatures characteristic of physiological processes (e.g., development [18], aging [19][20][21][22]) and pathological states (e.g., cardiovascular diseases [23], cancer [24], fibrosis [25][26][27]). However, existing proteomic approaches present limitations.…”