Figure 6.

Schematic model on possible formation of unprocessed late endosomal-like vesicles and podocyte damage due to fusion and maturation defects in the autophagic and endo-lysosomal pathway. (A) Normal condition: Intracellular trafficking paths of the endocytic and autophagic pathway and their common end route—the lysosome. Late endosomes, autophagosomes, and amphisomes fuse with lysosomes and become autoendolysosomes. Autoendolysosomes are recycled by lysosome reformation. Podocyte is healthy and builds foot processes and SD. (B) Rab7 deletion early stage: Inhibited fusion of lysosomes with late endosomes leads to the accumulation of unprocessed late endosomal-like vesicles (ULLVs) as observed in mice and human podocytes. Autophagosomes do not fuse with lysosomes and, therefore, accumulate (double-membraned structures observed in mice). Lysosome maturation and reformation may be disturbed and result in an accumulation of autoendolysosomes, as especially seen in Drosophila but also in human podocytes. (C) Rab7 deletion late stage: The continuing accumulation of vesicles within the podocyte leads to the loss of foot processes and SDs due to (1) sterically hindrance in cell trafficking, (2) less recycled material/resources, and (3) the accumulation of toxic waste products from unprocessed vesicles. A, autophagosome; AL, autoendolysosome; Amp, amphisome; EE, early endosome; FP, foot process; FPE, foot process effacement; LE, late endosome; LY, lysosome; N, nucleus; Pod, podocyte; SD, slit diaphragm; ULLV, unprocessed late endosomal-like vesicle. Figure 6 can be viewed in color online at www.jasn.org.