Peroxisomal Degradation Correlates with the Progression of Kidney Injury in a UUO Mouse Model

The kidney is an organ rich in peroxisomes, which play a pivotal role in fatty acid oxidation and ROS decomposition. Importantly, peroxisomal dysfunction contributes to the development and progression of various renal diseases. Therefore, we aimed to elucidate whether peroxisomes affect renal damage and fibrosis over time using a unilateral ureteral obstruction (UUO) mouse model.

Expression levels of peroxisome-related factors and ROS- and hypoxia-related genes in UUO mice were measured in a time-dependent manner.

UUO led to renal damage and fibrosis progression over time; it significantly increased the protein expression levels of ATG5 and ATG7, while it decreased PMP70 and PEX14 protein expression. In particular, UUO increased the protein expression level of pexophagy receptor NBR1. Although the number of peroxisomes decreased, the protein expression levels of peroxisomal biogenesis-related proteins such as PEX11b, PEX16, and PEX19 remained constant. Decreased lipid metabolism due to reductions in ACOX1, DBP, and catalase caused by UUO and increased ROS production through peroxisomal degradation and mitochondrial antioxidant enzyme dysfunction were observed. Additionally, HIF-1α protein levels gradually increased in the UUO mice, whereas those of HIF-2α initially increased and then decreased.

UUO is characterized by a progressive, chronological reduction in peroxisomal markers. Our findings indicate that peroxisomal degradation and associated metabolic dysfunction are tightly correlated with the progression of kidney injury and fibrosis, suggesting a potential involvement of compromised peroxisomal homeostasis in renal pathogenesis rather than proving a direct causal mechanism. Maintaining peroxisomal quality control may nevertheless represent a potential therapeutic avenue for chronic kidney disease.