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Abstract: PO0695

Dysregulation of Thiosulfate Thiotransferase Pathway Contributes to Tubulointerstitial Injury of Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Zhang, Jiaxiu, Institute of Nephrology, Southeast University, Nan Jing City, JIang Su Province, China
  • Ma, Kun ling, Institute of Nephrology, Southeast University, Nan Jing City, JIang Su Province, China
Background

Tubulointerstitial injury plays an important role in the progression of diabetic nephropathy (DN), and its severity is closely related to the prognosis of DN. Thiosulfate thiotransferase (TST) is a key enzyme that mediates protein S-sulfhydrylation and maintains mitochondrial metabolic homeostasis. This study aimed to investigate the role of TST in tubulointerstitial injury of DN and to explore its potential mechanisms.

Methods

Sodium thiosulfate (STS)-treated diabetic mice, adeno-associated virus with TST overexpression transfected diabetic mice, and cell culture model of HK-2 cells transfected by lentivirus with TST overexpression were used for experiments. The protein S-sulfhydration of very long-chain acyl-CoA dehydrogenase (VLCAD) was checked by Western blotting and mass spectrometry analysis. Tubular mitochondrial mitochondrial fatty acid β oxidation (FAO) was checked by 13C labeling combined with mass spectrometry and Seahorse assay. Epithelial mesenchymal transition (EMT) related molecules of tubular epithelial cells were evaluated by immunofluorescent staining and Western blotting.

Results

Our results showed that the expression of TST was decreased in kidneys of diabetic mice and in high glucose-stimulated HK-2 cells, which was significantly correlated with decreased E-cadherin and increased protein expression of collagen I, fibronectin, and α-SMA. Furthermore, the down-regulation of TST expression led to the FAO dysfunction in kidneys of diabetic mice and in high glucose-stimulated HK-cells. On the contrary, STS treatment or overexpression of TST alleviated albuminuria and tubulointerstitial injury. The expression of collagen I, fibronectin, and α-SMA in TST transfected diabetic mice or HK-2cells were significantly decreased, while E-cadherin expression was increased. Further analysis showed that pharmacological inhibition of STS or overexpression of TST improved mitochondrial FAO dysfunction and tubulointerstitial injury in diabetic mice and in high glucose-stimulated HK-2 cells, which was mainly through the increased S-sulfhydrylation modification of VLCAD.

Conclusion

These findings demonstrated that down-regulation of TST expression mediated the decrease of S-sulfhydrylation modification of VLCAD, which led to mitochondrial FAO dysfunction and then exacerbated the progression of tubulointerstitial injury in DN.