Abstract
Focal segmental glomerulosclerosis (FSGS) is a histopathologic lesion caused by a dysfunction and loss of podocytes. Podocytes as postmitotic cells, rely on lysosomes to maintain their structural and functional integrity and on mitochondria to adapt their metabolic needs. The importance of lysosomes and mitochondria in glomerular diseases is widely accepted, their time-dependent involvement during pathogenic events of FSGS remain unknown. The inducible mouse model of podocyte-specific Nphs2 deletion allowing the study of the time-dependent sequence of pathogenic events. Earliest alterations were overserved at 5 days after FSGS induction and comprise a very low number of glomeruli with foot process effacement and tuft adhesions to the Bowmans capsule, a lysosome stress response, mitochondria injury and higher chemokine CXCL1 expression. At 9 days after FSGS induction, increased glomerular injury with additional mesangial proliferations, higher abundance of lysosomes, galectin-3 and mitochondria stress occurred. At 17 days after FSGS induction, severe glomerular injury with additional podocyte flattening, glomerular sclerosis and hyaline deposits together with ER stress were evident. In summary, lysosome stress response and mitochondria injury are the earliest events in FSGS development. Having a role in signaling and inflammation, both lysosomes and mitochondria may facilitate the initiating event of inflammation with subsequent chemokine CXCL1 action within the podocyte. Endoplasmic reticulum stress however, may maintain podocytes injury and contribute to the disease conservation of FSGS.