The diabetic microenvironment causes mitochondrial oxidative stress in glomerular endothelial cells and pathological crosstalk with podocytes.

摘要: In the setting of diabetes mellitus, mitochondrial dysfunction and oxidative stress are important pathogenic mechanisms causing end organ damage, including diabetic kidney disease (DKD), but mechanistic understanding at a cellular level remains obscure. mouse models DKD, glomerular endothelial cell (GEC) precedes albuminuria contributes to neighboring podocyte dysfunction, implicating GECs in breakdown filtration barrier. following studies we wished explore by which become dysfunctional milieu, impact podocytes. Mouse were exposed high glucose media (HG) or 2.5% v/v serum from mice non-diabetic controls, evaluated for function (oxygen consumption), structure (electron microscopy), morphology (mitotracker), superoxide (mitoSOX), as well accumulation oxidized products (DNA lesion frequency (8-oxoG, endo-G), double strand breaks (γ-H2AX), (NOS activity), autophagy (LC3) apoptotic death (Annexin/PI; caspase 3). Supernatant transfer experiments podocytes performed establish effects on survival transwell determine co-culture. Diabetic specifically causes release GECs. There is rapid oxidation DNA loss biogenesis without death. Many these blocked mitoTEMPO selective anti-oxidant. Secreted factors sufficient cause apoptosis supernatant experiments, co-culture this did not occur when had been previously treated with mitoTEMPO. Dissecting environment individual cell-types glomerulus indicates that pathological increased levels GEC. These indicate GEC-signaling barrier DKD.