Advani, S. L. | bioRxiv Science

bioRxiv2026

Sex-dependent control of renal tubular homeostasis and stress tolerance by KDM6A

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@9186b8org.highwire.dtl.DTLVardef@23d4cborg.highwire.dtl.DTLVardef@67741eorg.highwire.dtl.DTLVardef@1f85dc7_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

Splicing factor proline- and glutamine-rich (SFPQ) protein causes transcriptional repression of SNAIL to counteract TGF-β signaling

TGF-{beta} is known to regulate several embryonic and adult signaling pathways. Moreover, this signaling pathway regulates several cellular functions including differentiation, cell division, angiogenesis, hematopoiesis, and cell migration. However, studies suggest that an uncontrolled activation of TGF-{beta} signaling may contribute to many human diseases. Therefore, counter-regulatory mechanism(s) to restrain abrupt TGF-{beta} activation during cellular homeostasis is necessary to maintain an adequate balance of TGF-{beta} downstream signaling. TGF-{beta} through Smad complex activation causes transcriptional regulation of many transcription factors including Snail which act as an immediate-early response gene in TGF-{beta} signaling. Herein, for the first time, we report that Splicing factor proline- and glutamine-rich (SFPQ), an RNA binding paraspeckles-associated protein works as a transcriptional repressor of Snail. We first confirmed a significant reduction in the expression level of SFPQ in the kidney glomeruli of rats that underwent subtotal nephrectomy. Endothelial cells (EC) treated with TGF-{beta} exhibited loss of SFPQ protein level without altering its transcript level. Inhibition of proteasomal or autophagosome-lysosome pathway revealed ubiquitination-dependent proteasomal degradation of SFPQ upon TGF-{beta} challenge. Prior to degradation, TGF-{beta} treatment resulted in the cytosolic export of SFPQ thereby diminishing nuclear SFPQ level. Knockdown of SFPQ augmented TGF-{beta}-dependent increase in Snail level while overexpression of SFPQ reversed TGF-{beta} induced Snail expression. Although SFPQ exhibited association with many transcription factors including Smad2/3, Smad4, and N1-ICD which regulate Snail gene expression, TGF-{beta} failed to alter the association of SFPQ with these transcription factors. Instead, through ChIP-qPCR analysis, we confirmed the enrichment of SFPQ in E-box promoter region and coding region proximal to TSS of the Snail gene. This study is the first to report SFPQ as a transcriptional repressor of Snail thereby regulating TGF-{beta} signaling during cellular homeostasis.

biochemistry↗