blister and Edema

Mutations in the MYH9 gene, coding for the non-muscle myosin heavy chain IIA (NMHC-IIA), are responsible for syndromes characterized by macrothrombocytopenia associated with deafness, cataracts, and severe glomerular disease. Electron microscopy of renal biopsies from these patients found glomerular abnormalities characterized by alterations in mesangial cells, podocytes, and thickening of the glomerular basement membrane. Knockout of NMHC-IIA in mice is lethal, and therefore little is known about the glomerular-related functions of Myh9. Here, we use zebrafish as a model to study the role and function of zNMHC-IIA in the glomerulus. Knockdown of zNMHC-IIA resulted in malformation of the glomerular capillary tuft characterized by few and dilated capillaries of the pronephros. In zNMHC-IIA morphants, endothelial cells failed to develop fenestrations, mesangial cells were absent or reduced, and the glomerular basement membrane appeared nonuniformly thickened. Knockdown of zNMHC-IIA did not impair the formation of podocyte foot processes or slit diaphragms; however, podocyte processes were less uniform in these morphants compared to controls. In vivo clearance of fluorescent dextran indicated that the glomerular barrier function was not compromised by zNMHC-IIA knockdown; however, glomerular filtration was significantly reduced. Thus, our results demonstrate an important role of zNMHC-IIA for the proper formation and function of the glomerulus in zebrafish.

Topics: Animals; Blood Platelets; Dextrans; Edema; Endothelial Cells; Fluorescein-5-isothiocyanate; Fluorescent Dyes; Gene Expression Regulation, Developmental; Gene Knockdown Techniques; Genotype; Glomerular Basement Membrane; Glomerular Filtration Rate; Heterocyclic Compounds, 4 or More Rings; Kidney Glomerulus; Larva; Nonmuscle Myosin Type IIA; Permeability; Phenotype; Podocytes; Recombinant Proteins; Time Factors; Zebrafish; Zebrafish Proteins