Glomerular basement membrane structural integrity dictates trans-tissue deposition of laminin in the kidney

• Laminin-α2 deposits in the structurally defective glomerular basement membrane • Laminin-α2 and other extracellular matrix proteins circulate in the blood • Basement membrane structure dictates deposition of circulating laminin-α2 • Evidence for trans -tissue deposition of basement membrane proteins in mammals Laminin-α2 deposits in the structurally defective glomerular basement membrane Laminin-α2 and other extracellular matrix proteins circulate in the blood Basement membrane structure dictates deposition of circulating laminin-α2 Evidence for trans -tissue deposition of basement membrane proteins in mammals Basement membranes (BMs) are specialized extracellular matrices (ECMs) essential for tissue structure and function. In non-vertebrates, ECM components can be produced both locally and by distant tissues. In contrast, mammalian ECM has traditionally been considered to originate predominantly from adjacent or tissue-resident cells. The kidney glomerular basement membrane (GBM), composed of laminin-α5β2γ1 and collagen-α3α4α5(IV), is produced by neighboring cells and functions as a filtration barrier. Alport syndrome, a genetic kidney disease, is characterized by GBM structural defects and ectopic laminin-α2 deposition, but the source of this laminin remains unknown. Here, using CRISPR-Cas9 transgenic models, we demonstrated that ectopic laminin-α2 in GBM originates not from local kidney cells but from the circulation. Furthermore, laminin-α2 in the mesangium partially derives from circulating sources even under healthy conditions. Our findings uncover a non-cell-autonomous mechanism whereby GBM integrity regulates circulating protein incorporation, revealing a trans -tissue regulation of BM composition in mammals.