Altered expression, but small contribution, of the histone demethylase KDM6A in obstructive uropathy in mice

Epigenetic processes have emerged as important modulators of kidney health and disease. Here, we studied the role of KDM6A (a histone demethylase that escapes X-chromosome inactivation) in kidney tubule epithelial cells. We initially observed an increase in tubule cell Kdm6a mRNA in male mice with unilateral ureteral obstruction (UUO). However, tubule cell knockout of KDM6A had relatively minor consequences, characterized by a small reduction in apoptosis, increase in inflammation and downregulation of the peroxisome proliferator-activated receptor (PPAR) signaling pathway. In proximal tubule lineage HK-2 cells, KDM6A knockdown decreased PPARγ coactivator-1α (PGC-1α) protein levels and mRNA levels of the encoding gene, PPARGC1A. Tubule cell Kdm6a mRNA levels were approximately 2-fold higher in female mice than in male mice, both under sham and UUO conditions. However, kidney fibrosis after UUO was similar in both sexes. The findings demonstrate Kdm6a to be a dynamically regulated gene in the kidney tubule, varying in expression levels by sex and in response to injury. Despite the context-dependent variation in Kdm6a expression, knockout of tubule cell KDM6A has subtle (albeit non-negligible) effects in the adult kidney, at least in males.