Role of HDAC6 in Transcription Factor EB Mediated Clearance of Misfolded Proteins in Chronic Kidney Disease

The autophagy-lysosomal pathway is a homeostatic mechanism to prevent the accumulation of misfolded proteins. Here, we observed a downregulation in a master regulator of autophagy, transcription factor EB (TFEB) and an increase in misfolded protein accumulation in kidneys from humans with diabetic kidney disease and in subtotally nephrectomized (SNx) rats, pointing to dysregulated autophagy as a common occurrence in chronic kidney disease (CKD). In assessing methods to induce autophagy, we found that inhibition of histone deacetylase 6 (HDAC6) caused hyperacetylation and nuclear translocation of TFEB, and reduced cell death in cultured proximal tubule cells. Similarly, in SNx rats, HDAC6 inhibition decreased misfolded protein accumulation in tubule epithelial cells, attenuated tubule cell death, diminished fibrosis and blunted proteinuria. These findings point to the occurrence of dysregulated autophagy in CKD and identify HDAC6 inhibitors as a novel method to activate TFEB mediated upregulation of the autophagy-lysosomal pathway that may confer renoprotective benefits.M.Sc