Nicotinamide Nucleotide Transhydrogenase deficiency and genetic susceptibility to high glucose-mediated peritoneal injury

The genetic predisposition to high glucose-induced injury to the peritoneal membrane (PM) during peritoneal dialysis (PD) and its mechanistic implications are of substantial clinical interest. We compared PD-induced peritoneal injury and fibrosis between two closely related mouse substrains. Compared to C57BL/6J mice, C57BL/6N mice exhibited significantly greater susceptibility to PD fluid-induced peritoneal damage, as indicated by the loss of the mesothelial cell monolayer, peritoneal membrane fibrosis, neoangiogenesis, inflammatory response, infiltration of pro-inflammatory M1 macrophages, and reduced ultrafiltration capacity. Given that C57BL/6J mice display a spontaneous loss-of-function mutation in the mitochondrial enzyme nicotinamide nucleotide transhydrogenase (NNT), which plays a critical role in maintaining mitochondrial redox balance and energy metabolism- both of which are severely challenged during PD- we conducted further NNT silencing experiments. Knockdown of NNT prevented the mitochondrial accumulation of reactive oxygen species (ROS), reduced pro-inflammatory mediator release in mouse peritoneal mesothelial cells, prevented M1 macrophage polarization in peritoneal macrophages, and strongly decreased proliferation under high glucose conditions in NIH-3T3 fibroblasts. We observed a reverse NNT reaction in fibroblasts, contributing to high glucose (HG)-induced mitochondrial reactive oxygen species (ROS) accumulation. Our results indicate decreased genetic susceptibility of C57BL/6J mice to PD-induced PM damage compared to C57BL/6N mice. Additionally, our in vitro experiments identify NNT, which is deficient in C57BL/6J mice, as a potential therapeutic target for PD-associated peritoneal injury.