Sex-dependent control of renal tubular homeostasis and stress tolerance by KDM6A
Hong, L. Y.; Batchu, S. N.; Tran, D. T.; Syeda, M. Z.; Advani, S. L.; Liu, Y.; Pacis, A.; Petrotchenko, E. V.; Borchers, C. H.; Yuen, D. A.; Advani, A.
Show abstract
Biological sex is an important determinant of kidney disease susceptibility and outcomes. The epigenetic modifier KDM6A is an X chromosome-expressed lysine demethylase and molecular scaffold that escapes X chromosome inactivation. Here, we compared the effects of deletion of KDM6A from kidney tubule epithelial cells in female and male mice (KDM6ATubKO). Knockout of KDM6A from tubule cells aggravated kidney fibrosis caused by unilateral ureteral obstruction (UUO) in female mice, whereas male mice were unaffected by KDM6A absence. Unexpectedly, female (but not male) KDM6ATubKO mice developed spontaneous glucosuria that, when stressed by ligation of one ureter, presented as polyuria and a Fanconi renotubular syndrome-like picture affecting the unobstructed kidney. Absence of KDM6A from tubule epithelial cells of female mice caused mitochondrial circularization, tubule cell vacuolization with focal atrophy and lymphoid infiltration, and diminished sodium/glucose cotransporter 2 (SGLT2). Spatial transcriptomics and untargeted metabolomics revealed that knockout of KDM6A in female mice caused a shift in gene programs and metabolic pathways indicative of tubule cell metabolic dysfunction. In male mice, transcripts of the Y chromosome-expressed gametolog of Kdm6a, Uty were present in tubule epithelial cells at levels comparable to Kdm6a and they were upregulated with UUO. In summary, KDM6A is essential for normal tubule epithelial cell homeostasis in females but not in males. KDM6A and UTY are a dynamically regulated X-Y gene pair with at least partial compensatory overlap in function necessary for the preservation of kidney health and stress tolerance. Graphical abstract. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/740137v1_ufig1.gif" ALT="Figure 1000"> View larger version (29K): org.highwire.dtl.DTLVardef@7d26a4org.highwire.dtl.DTLVardef@740972org.highwire.dtl.DTLVardef@1851f7org.highwire.dtl.DTLVardef@ad6485_HPS_FORMAT_FIGEXP M_FIG C_FIG
Matching journals
The top 2 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Farnesoid X receptor agonism prevents neutrophil extracellular traps via reduced sphingosine-1-phosphate in chronic kidney disease 97%
- Cystinosin deficient rats recapitulate the phenotype of nephropathic cystinosis 97%
- Knockout of the V-ATPase interacting protein Tldc2 in B-type kidney intercalated cells impairs urine alkalinization 96%
Similar papers in this journal
- Tubular STAT3 limits renal inflammation in autosomal dominant polycystic kidney disease 97%
- Proximal tubule cells contribute to the thin descending limb of the loop of Henle during mouse kidney development 97%
- Hnf4a is required for the development of Cdh6-expressing progenitors into proximal tubules in the mouse kidney 97%
Similar papers in this journal
Similar papers in this journal
- Distinct cell types along thick ascending limb express pathways for monovalent and divalent cation transport 96%
- NAD+ activates renal metabolism and protects from chronic kidney disease in a model of Alport syndrome 96%
- Loss of long-chain acyl-CoA dehydrogenase protects against acute kidney injury 96%
Similar papers in this journal
- Deficiency of peroxisomal L-bifunctional protein (EHHADH) causes male-specific kidney hypertrophy and proximal tubular injury in mice 95%
- Endothelial Cell-Specific Molecule-1 Inhibits Albuminuria in Diabetic Mice 95%
- Pkd1 mutation has no apparent effects on peroxisome structure or lipid metabolism 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.