Impairment of Proteasome Function in Podocytes Leads to CKD.

Background: The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal system (APLS) are major intracellular degradation procedures. The importance of the APLS in podocytes is established, but the role of the UPS is not well understood.

Methods: To investigate the role of the UPS in podocytes, mice were generated that had deletion of (), which encodes an essential regulatory subunit required for construction of the 26S proteasome and its deubiquitinating function.

Results: mice showed albuminuria and glomerulosclerosis, leading to CKD. Impairment of proteasome function caused accumulation of ubiquitinated proteins and of oxidative modified proteins, and it induced podocyte apoptosis. Although impairment of proteasome function normally induces autophagic activity, the number of autophagosomes was lower in podocytes of 3 mice than in control mice, suggesting the autophagic activity was suppressed in podocytes with impairment of proteasome function. In an study, antioxidant apocynin and autophagy activator rapamycin suppressed podocyte apoptosis induced by proteasome inhibition. Moreover, rapamycin ameliorated the glomerular injury in the mice. The accumulation of ubiquitinated proteins and of oxidative modified proteins, which were detected in the podocytes of mice, is a characteristic feature of aging. An aging marker was increased in the podocytes of mice, suggesting that impairment of proteasome function promoted signs of aging in podocytes.

Conclusions: Impairment of proteasome function in podocytes led to CKD, and antioxidants and autophagy activators can be therapeutic agents for age-dependent CKD.