Mesangial Cell–Derived Extracellular Matrix Protein 1 Is Essential for Maintaining Mesangial Matrix Homeostasis and Glomerular Architecture

KEY POINTS: Extracellular matrix protein 1 is specifically expressed in glomerular mesangial cells in both human and mice. Loss of extracellular matrix protein 1 leads to excessive mesangial matrix expansion and disrupted glomerular architecture. Extracellular matrix protein 1 binds integrin α 8 β 1 to stabilize mesangial cell adhesion to the mesangial matrix and glomerular basement membrane. BACKGROUND: The mesangium consists of mesangial cells and mesangial matrix that maintain normal glomerular structure and function. The mechanisms by which mesangial cells regulate mesangial matrix dynamics remain poorly understood. This study investigated the role of mesangial cell-derived extracellular matrix protein 1 (ECM1) in regulating mesangial matrix homeostasis and glomerular structure in mice. METHODS: Immunofluorescence and single-nucleus RNA sequencing were used to clarify the ECM1 expression pattern in kidney. Global and tamoxifen-inducible Ecm1 -knockout (KO) mice demonstrated the in vivo function of Ecm1 . Immunoprecipitation, mass spectrometry, and RNA-seq were used to reveal the mechanism by which ECM1 regulates mesangial matrix homeostasis. RESULTS: snRNA-seq and immunofluorescence revealed that ECM1 was specifically expressed in glomerular mesangial cells and downregulated in diabetic kidney disease and IgA nephropathy. Genetic deletion of Ecm1 in mice resulted in mesangial matrix expansion at 4 and 8 weeks of age, whereas early stages appeared unaffected. Similarly, tamoxifen-induced global deletion of Ecm1 in 4-week-old mice led to a trend toward mesangial matrix expansion. Transcriptomic profiling and immunofluorescence confirmed substantial alterations of the mesangial matrix components in Ecm1 -KO kidneys. As a result, histological examination showed profound glomerular abnormalities in Ecm1 -KO mice. Ecm1 deficiency also elevated TGF β 1 expression and downstream signaling, likely contributing to the excessive collagen deposition in glomeruli. Mechanistically, ECM1 interacted with integrin α 8 β 1 to promote mesangial cell-matrix adhesion, and loss of this interaction led to mesangial cell disaggregation and detachment from glomerular basement membrane, thereby promoting glomerular pathology. Notably, adeno-associated virus-mediated ECM1 expression in vivo effectively rescued kidney dysfunction in Ecm1 -KO mice. CONCLUSIONS: ECM1 was highly expressed in glomerular mesangial cells. Loss of Ecm1 led to altered mesangial matrix composition, matrix expansion, and glomerular abnormalities, while restoration of ECM1 expression reversed these defects, demonstrating an essential role of mesangial cell-derived ECM1 in preserving normal mesangial homeostasis and glomerular structure in mice.