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Abstract: PO0705

DPP4 Inhibitors Ameliorates Endoplasmic Reticulum Stress in Diabetic Kidney Disease Through Upregulation of SIRT1

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Zhang, Qunzi, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China, China
  • Fan, Ying, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China, China
  • Wang, Niansong, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China, China
Background

Endoplasmic Reticulum (ER) stress plays vital roles in the progression of diabetic kidney disease (DKD), and Dipeptidyl peptidase-4 (DPP4) inhibitors are widely used antihyperglycemic agents, further exerting renal beneficial effects in DKD, but the precise mechanism underlying the disruption of these processes remains unclear. We examined whether SIRT1/STAT3 pathway regulated ER stress in the progression of DKD.

Methods

In vivo, male DBA2/J mice were injected by streptozotoxin to form diabetic mice models, then sitagliptin(Sita) was gavaged to inhibit DPP4. We collected and analyzed kidney samples, urine and serum. In vitro, human HK-2 cells were exposed to human serum albumin (HSA), then regulated DPP4, SIRT1 with inhibitors, siRNAs and mutant plasmids. Outcome measures included ER stress, expression of GRP78, CHOP, phosphorylation of PERK (p-PERK), cleaved caspase3 (c-CASP3), SIRT1 and STAT3.

Results

ER stress were observed both in diabetic mice and in HSA-induced human HK-2 cells, as reflected by notably increased GRP78, CHOP, highly phosphorylation of PERK (p-PERK) and elevated cleaved caspase3 (c-CASP3), whereas Sita effectively attenuated these disorders. Meanwhile, Inhibited DPP4 increased the expression of SIRT1 both in vivo and in vitro, which has a protective effect on diabetic ER homeostasis, whereas decreased SIRT1 accentuated ER stress. Moreover, partly through elevated SIRT1, Sita regulated mitochondrial STAT3 and phosphorylation of STAT3 at ser727,which is required for STAT3 to import into mitochondria. . Our work found that the inhibition of DPP4 ameliorated ER stress in DKD partly through SIRT1/STAT3 signaling pathway.

Conclusion

The results suggested a novel mechanism links the DPP4 enzyme to ER stress during tubular injury in DKD and highlight that SIRT1/STAT3 pathway may become a potential target for managing DKD.

Funding

  • Government Support – Non-U.S.