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Abstract: FR-PO190

Sitagliptin Ameliorated Mitochondrial Dysfunction in Diabetic Kidney Disease via SDF-1α/CXCR4/STAT3

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
  • He, Li, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
  • Fan, Ying, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
  • Wang, Niansong, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
Background

Dipeptidyl peptidase-4 (DPP-4) inhibitors, which can hinder degradation of bioactive incretins, have been developed as a new type of glycemic control agent in both clinical and basic studies. Moreover, recent studies indicate that DPP4 inhibitors can improve albuminuria suggesting a favorable effect on kidney,but the exact mechanism remains unclear. We test whether an SDF-1α/CXCR4/STAT3 signaling pathway regulates mitochondrial dysfunction when inhibited DPP4 in DKD.

Methods

In vivo, male DBA2/J mice were subjected to streptozotoxin to form diabetic mice models, then sitagliptin was used for gavage to inhibit DPP4. We collected and analyzed kidney samples, urine and serum. In vitro, human HK2 cells were exposed to human serum albumin (HSA), then regulated DPP4, CXCR4 and STAT3 with inhibitors, siRNAs and mutant plasmids. Outcome measures included mitochondrial dynamics, expression of SDF-1α, CXCR4 and STAT3, mitochondrial membrane potential and mitochondrial ROS production.

Results

In diabetic mice, Sitagliptin decreased renal DPP4 expression, improved renal function, attenuated tubular damage, and partly attenuated mitochondrial dysfunction, yet sitagliptin cannot significantly control glycemia of these mice. Besides, sitagliptin obviously upregulated SDF-1α/CXCR4 expression and mitochondrial STAT3. In vitro, HK2 cells exposed to HSA exhibited increased DPP4 accompanied by mitochondrial fragmentation, altered mitochondrial dynamics and elevated mitochondrial ROS production. Inhibited DPP4 improves SDF-1α/CXCR4 expression, which has a positive effect on diabetic mitochondrial function, whereas upregulated DPP4 aggravated these mitochondrial perturbations. Moreover, partly through SDF-1α/CXCR4 pathway, inhibition of DPP4 regulated mitochondrial STAT3 and phosphorylation of Ser727 in STAT3,which is required for STAT3 to import into mitochondria. Our work found that the inhibition of DPP4 ameliorated mitochondrial dysfunction in DKD partly through SDF-1α/CXCR4/STAT3 signaling pathway.

Conclusion

The results suggest a novel mechanism linking DPP4 to impair mitochondrial quality control during tubular injury in the pathogenesis of DKD and suggest SDF-1α/CXCR4/STAT3 pathway may become a potential therapeutic point to ameliorate DKD.

Funding

  • Government Support - Non-U.S.