# Nicotinamide nucleotide transhydrogenase deficiency and genetic susceptibility to high glucose‐mediated peritoneal injury in mice

## TL;DR

This study shows that a genetic deficiency in the NNT enzyme protects mice from peritoneal damage caused by high-glucose dialysis fluids.

## Contribution

The study identifies NNT as a key regulator of mitochondrial redox balance and a potential therapeutic target for peritoneal dialysis injury.

## Key findings

- Nnt-deficient C57BL/6J mice showed reduced peritoneal injury, inflammation, and fibrosis compared to Nnt-competent C57BL/6N mice.
- NNT silencing in vitro reduced ROS generation, M1 polarization, and profibrotic signaling in response to high glucose.
- NNT can switch to a pro-oxidative 'reverse mode' under high-glucose conditions, contributing to peritoneal injury.

## Abstract

The genetic predisposition to high glucose‐induced peritoneal membrane (PM) injury during peritoneal dialysis (PD) and its mechanisms are of substantial clinical interest. We compared PD‐induced peritoneal injury between two closely related mouse substrains, C57BL/6J and C57BL/6N, which differ in the function of the mitochondrial enzyme nicotinamide nucleotide transhydrogenase (NNT). Nnt(+/+) C57BL/6N mice exhibited significantly greater susceptibility, as indicated by mesothelial cell loss, fibrosis, neoangiogenesis, inflammation, M1 macrophage infiltration, and reduced ultrafiltration. To further investigate NNT's role, we silenced NNT in vitro. Knockdown prevented mitochondrial ROS accumulation, reduced pro‐inflammatory mediator release in mesothelial cells, inhibited M1 polarization in macrophages, and impaired fibroblast proliferation under high glucose. We also observed a reverse NNT reaction in fibroblasts, contributing to glucose‐induced ROS. Our findings indicate reduced genetic susceptibility of Nnt(−/−) C57BL/6J mice to PD‐induced PM damage and identify NNT as a potential therapeutic target for PD‐associated peritoneal injury.

High‐glucose peritoneal dialysis (PD) fluid induces oxidative stress, inflammation, and fibrosis in the peritoneum. In vivo, Nnt‐deficient C57BL/6J mice showed significantly reduced PD‐induced peritoneal injury, inflammation, and fibrosis compared with Nnt‐competent C57BL/6N controls. Complementary in vitro NNT‐silencing experiments in peritoneal mesothelial cells, macrophages, and fibroblasts demonstrated reduced high‐glucose‐induced ROS generation, M1 polarization, and profibrotic signaling. Together, these data identify NNT as a key regulator of mitochondrial redox balance that may switch to a pro‐oxidative “reverse mode” under high‐glucose conditions, thereby representing a potential therapeutic target to prevent PD‐associated peritoneal damage.