Conditional Knockout Kdm2a Reveals Crucial Involvement in Development and Function of Kidney Collecting Ducts

Lysine-specific histone demethylase 2 (Kdm2a) is essential for histone modifications involved in development and associated diseases. Nevertheless, the specific functions of Kdm2a in renal development and pathology remain largely unexplored. This study aimed to elucidate the roles of Kdm2a in sustaining the biological functions of the kidney by generating mutant mice with Kdm2a deletion using the Aqp2-cre/Loxp system. Our findings showed that Kdm2a is widely expressed across various mouse tissues, with particularly high expression in the kidney's cortex and medulla, surpassing that in other tissues. Despite no observable effects on morphology or survival following the conditional knockout of Kdm2a, there was a significant reduction in body weight and bilateral kidney weight compared to controls, most pronounced at the 5-week-old stage (p < 0.05). Post Kdm2a deletion, kidney metabolic functions were impaired, evidenced by altered levels of creatinine, urea, total cholesterol, and low-density lipoprotein. Histological examination revealed that Kdm2a-null kidneys exhibited signs of dysfunction, characterized by macrophage infiltration, fibrosis, inflammatory cell infiltration, and mild thrombosis. Further studies revealed that the expression of chemokine- and pro-inflammatory cytokine-related genes Il-6, Il-8, Tnf-a, and Il-1β was significantly increased in the kidneys of Kdm2a cKO mice compared with controls (p < 0.05). Additionally, the expression of reabsorption-related genes (Aqp-3, Aqp-5, and Aqp-8) was markedly downregulated in Kdm2a-deficient kidneys compared with controls (p < 0.05). Collectively, these findings suggest that Kdm2a is crucial for maintaining kidney function and development, partly through the suppression of inflammation and regulation of gene expression. However, the underlying molecular mechanisms of Kdm2a in kidney development warrant further investigation.