Semaglutide improves podocyte foot process ultrastructure in db/db UNx-ReninAAV mice. (A) Semaglutide monotherapy (30 nmol/kg, s.c., q.d. n = 15) and combined lisinopril treatment (30 mg/kg, p.o., n = 14) reduces severity of podocyte foot process effacement in db/db UNx-ReninAAV mice, as indicated by increased filtration slit density (FSD). Vehicle-dosed (s.c, q.d.) db/db UNx-ReninAAV mice (n = 15) served as controls. ** p < 0.01, *** p < 0.001 vs. vehicle-dosed db/db UNx-ReninAAV mice (one-way ANOVA). The FSD of 20 glomeruli was determined for every animal. (B) Upper panels: Photomicrographs of podocin-stained glomeruli obtained by wide field microscopy and after SIM reconstruction. The 3D-SIM (z-stack) images of slit diaphragms were colorized according to their position on the z-axis (µm). Lower panels: As shown by increased magnification, the space between podocin-stained capillary loops was increased in vehicle-dosed db/db UNx-ReninAAV mice, indicative of aberrant foot process architecture with reduced FSD. Compared to vehicle controls, semaglutide and semaglutide + lisinopril significantly increased FSD, hence improving podocyte health in db/db UNx-ReninAAV mice. Scale bars, 5 µm.