Induction of PDCD4 by albumin in proximal tubule epithelial cells potentiates proteinuria-induced dysfunctional autophagy by negatively targeting Atg5.

The precise molecular mechanism of autophagy dysfunction in type 1 diabetes is not known. Herein, the role of programmed cell death 4 (PDCD4) in autophagy regulation in the pathogenesis of diabetic kidney disease (DKD) in vivo and in vitro was described. It was found that Pdcd4 mRNA and protein was upregulated in the streptozotocin (STZ)-induced DKD rats. In addition, a unilateral ureteral obstruction mouse model displayed an upregulation of PDCD4 in the disease group. kidney biopsy samples of human DKD patients showed an upregulation of PDCD4. Furthermore, western blotting of the STZ-induced DKD rat tissues displayed a low microtubule-associated protein 1A/1B-light chain 3 (LC3)-II, as compared to the control. It was found that albumin overload in cultured PTEC could upregulate the expression of PDCD4 and p62, and decrease the expression of LC3-II and autophagy-related 5 (Atg5) proteins. The knockout of Pdcd4 in cultured PTECs could lessen albumin-induced dysfunctional autophagy as evidenced by the recovery of Atg5 and LC3-II protein. The forced expression of PDCD4 could further suppress the expression of crucial autophagy-related gene Atg5. Herein, endogenous PDCD4 was shown to promote proteinuria-induced dysfunctional autophagy by negatively regulating Atg5. PDCD4 might therefore be a potential therapeutic target in DKD.