Relevance of extracellular matrix and its receptors in mammalian nephrogenesis revealed by metanephric organ culture sysrem

Abstract

Mammalian nephrogenesis is modulated by a number of extracellular matrix (ECM) glycoproteins, integrins and cell adhesion molecules. We demonstrated the existence of integrins αvβ1, αvβ3, αvβ5 and αvβ6 in epithelial elements of developing nephrons. Fibrillin-1 is a putative ligand for integrin αvβ3, and tubulo-interstitial nephritis antigen (TIN-ag) is a ligand for integrins αvβ3 and α31. Fibrillin-1 and TIN-ag are also differentially expressed in the developing kidney. The inclusion of antisense oligonucleotide in a mouse kidney organ culture system indicated that the αv-related integrins and their ligands play an important role in mammalian nephrogenesis. Recently identified modulators of cell-matrix interactions, i.e. β-galactoside-binding mammalian lectins (galectins), are involved in cell-cell and cell-matrix interactions by cross-linking glycoconjugates located on the ECM and membrane-bound glycoproteins. We identified and cloned a new member of the galectins from embryonic kidneys, and designated it galectin-9. Since high glucose alters the expression of ECM proteins and integrins, we also investigated the influence of glucose on metanephric development. The presence of 30 mM D-glucose in metanephric organ culture induced dysmorphogenesis of the kidney accompanied by decreased expression of perlecan. Furthermore, we screened the genes differentially expressed under high glucose conditions in streptozotocin-induced newborn mouse kidneys by representational difference analysis of cDNA. We identified translocase of inner mitochondrial membrane (Tim44) and renal-specific oxido-reductase (RSOR). The roles of these molecules in glucose-induced dysmorphogenesis and the relationship with ECM-related molecules need to be addressed.