Kidney Week

Abstract: SA-PO438

Nicotinamide Nucleotide Transhydrogenase Is Critically Involved in High Glucose-Mediated Peritoneal Damage

Session Information

• Home Dialysis - 2
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Dialysis

• 802 Dialysis: Home Dialysis and Peritoneal Dialysis

Authors

• Ohse, Margarete Clara, Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Niedersachsen, Germany

Margarete Clara Ohse

• Rong, Song, Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Niedersachsen, Germany

Song Rong, MD

• Balzer, Michael S., Medical Department, Division of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany

Michael S. Balzer, MD

• Von Vietinghoff, Sibylle, Nephrology Section, Medical Clinic 1, University Hospital Bonn, Bonn, Nordrhein-Westfalen, Germany

Sibylle Von Vietinghoff, MD

• Haller, Hermann, Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Niedersachsen, Germany

Hermann Haller, MD

• Kiyan, Yulia, Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Niedersachsen, Germany

Yulia Kiyan, PhD

• Shushakova, Nelli, Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Niedersachsen, Germany

Nelli Shushakova, PhD

Group or Team Name

• Dept of Nephrology and Hypertension, Hannover Medical School.

Background

High glucose (HG)-induced mitochondrial dysfunction contributes to peritoneal membrane damage during peritoneal dialysis (PD). Nicotinamide Nucleotide Transhydrogenase (NNT) is critically involved in maintaining the mitochondrial redox balance and energy metabolism. The enzyme catalyzes the transfer of redox potential between the mitochondrial NAD(H) and NADP(H) pools by utilizing the inner mitochondrial membrane potential.

Methods

The role of NNT in peritoneal membrane damage was investigated in vivo using a mouse model of PD applied in C57BL/6N wild-type and NNT-deficient C57BL/6J mice. In vitro, NNT silencing was performed in mouse peritoneal mesothelial cell line (MPMC), mouse primary peritoneal macrophages and NIH3T3 fibroblasts.

Results

Exposure of the peritoneum to PD fluid in C57BL/6N mice resulted in the loss of the mesothelial cell monolayer, peritoneal membrane fibrosis, neoangiogenesis, an inflammatory response, and macrophage infiltration, which was paralleled by reduced ultrafiltration capacity. In contrast, C57BL/6J NNT-deficient mice demonstrated much less structural and no functional damage of the peritoneal membrane. In vitro, a reverse NNT reaction in fibroblasts has been shown to contribute to HG-induced mitochondrial ROS accumulation. NNT silencing prevented mitochondrial ROS accumulation, decreased pro-inflammatory mediator release from MPMC and fibroblasts, prevented pro-inflammatory M1 macrophage polarization, and strongly decreased fibroblast proliferation under HG conditions.

Conclusion

Acting in reverse mode NNT contributes significantly to HG-induced PM damage. Inhibition of NNT activity could have therapeutic implications.

Funding

• Government Support – Non-U.S.