Abstract
Disruption of lysosomal homeostasis contributes to the tubulopathy of diabetic nephropathy; however, its underlying mechanisms remain unclear. Herein, we report that decreased activity of transcription factor EB (TFEB) is responsible for the disturbed lysosome biogenesis and clearance in this pathological process. This was confirmed by the findings that insufficient lysosomal replenishment and damaged lysosomal clearance coincided with TFEB inactivation, which was mediated by mTOR hyperactivation in the renal tubular epithelial cells (TECs) of diabetic nephropathy. Furthermore, either TFEB overexpression or pharmacological activation of TFEB enhanced lysosomal clearance via promoting lysosomal biogenesis and protected TECs by reducing apoptosis in vitro. In addition, pharmacological activation of TFEB attenuated renal tubule injury, apoptosis, and inflammation in db/db mice. In conclusion, diabetes-induced mTOR activation represses TFEB function, thereby perturbing lysosomal homeostasis through impairing lysosomal biogenesis and clearance in TECs. Moreover, TFEB activation protects TECs from diabetic injuries via restoring lysosomal homeostasis.
Highlights
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and a threat to global health [1, 2]
Our results show that diabetesinduced mammalian target of rapamycin (mTOR) activation contributes to transcription factor EB (TFEB) dysfunction and perturbs lysosomal homeostasis by impairing lysosomal biogenesis and clearance in tubular epithelial cells (TECs)
As disruption of lysosomal homeostasis can lead to the tubulopathy of diabetic nephropathy, we evaluated whether decreased activity of TFEB is responsible for disturbed lysosome biogenesis and clearance in this pathological process
Summary
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and a threat to global health [1, 2]. Several novel agents targeting multifaceted pathogenic pathways of DN have been evaluated in recent clinical trials [3]. These agents include avosentan (a nonselective endothelin receptor antagonist), finerenone (a nonsteroidal mineralocorticoid receptor antagonist), baricitinib (a janus kinase 1/2 inhibitor), and selonsertib (an apoptosis signal-regulating kinase 1 inhibitor). Among medications that are already widely used in patients with DN, only a few antidiabetic drugs, including renin angiotensin system (RAS) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and glucagon-like peptide-1 receptor agonists, have demonstrated a potential renal benefits [4,5,6]. Growing evidence suggests that tubular cells are not a victim but a neglected mediator in renal fibrosis in DN [7,8,9,10]
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