Activation of Transcription Factor EB Alleviates Tubular Epithelial Cell Injury via Restoring Lysosomal Homeostasis in Diabetic Nephropathy

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.

TXNIP deficiency attenuates renal fibrosis by modulating mTORC1/TFEB-mediated autophagy in diabetic kidney disease

“…Overexpression of TFEB inhibits cisplatin-induced apoptosis by restoring autophagy in HK-2 cells [ 40 ]. In addition, pharmacological activation of TFEB attenuates renal tubule injury, apoptosis, and inflammation in db/db mice [ 18 ]. The present study showed that HG led to a reduction in TFEB nuclear translocation in HK-2 cells.…”

“…A previous study revealed that TFEB expression is decreased in the kidneys of patients with diabetic kidney disease [ 17 ]. TFEB activation prevents tubular epithelial cell injury by restoring lysosomal homeostasis in diabetic nephropathy [ 18 ]. Recent studies have revealed the crucial role of mTORC1 as a TFEB regulator [ 19 , 20 ].…”

Inhibition of Amino Acids Influx into Proximal Tubular Cells Improves Lysosome Function in Diabetes

“…In diabetes animal models such as C57BL/Ks db/db mice, TFEB overexpression or pharmacological activation of TFEB alleviates the tubular epithelial cell injuries by enhancing lysosomal clearance, promoting lysosomal biogenesis, and formation of autophagosomes. 21,22 The current investigation provides the insights into drug discovery related to diabetes, obesity, and DKD. b amyloid precursor protein cleavage enzyme 1 cleaved amyloid b (Ab), and the development of guanidine-based novel BACE1 inhibitors for the treatment and maintenance of Alzheimer disease was attempted; however, most of the studies were discontinued.…”

“…Finally, the reduced phosphorylated inactive form of TFEB in STZ-HFD-Cltrn2/y suggested the beneficial effects of TFEB activator, and this notion was suggested in the previous studies. 21,22 The limitation of current investigation is that it is inconclusive whether the improvement of renal tubular lesions is due to reduced AA influx or systemic metabolic improvements. To further confirm the results, the investigation of the effects of altered AA influx on mTORC1 activity and autophagy-lysosomal function by using proximal tubulespecific Cltrn knockout mice or primary cultured tubular cells isolated from wild and Cltrn knockout mice.…”

Phomopsischalins A–C, polycyclic-fused cytochalasins from the endophytic fungus Phomopsis sp. shj2 and their abilities to induce lysosomal function

“…Thus, targeting lysosomal function is a promising therapeutic strategy. 3 Identifying natural products that regulate lysosomal function is of remarkable medical interest. Cytochalasins are a large family of fungal polyketide synthase-non ribosomal peptide synthetase (PKS-NRPS) hybrid metabolites with a plethora of biological activities, including antimicrobial, 4,5 cytotoxic, [6][7][8] cancer immunotherapeutic, 9 immunoregulatory, 10 cytoskeleton inhibitory, [11][12][13] and neurotrophic activities, 14 and have aroused considerable interest.…”