GLIS3, a novel regulator of eicosanoid gene expression and metabolism in normal kidney and polycystic kidney disease

Loss of function of the Krüppel-like zinc finger transcription factor GLI-similar 3 (GLIS3) causes polycystic kidney disease (PKD) indicating that it plays a critical role in regulating normal kidney functions. The first postnatal month is accompanied with significant changes in gene expression and represents a key period in kidney development as well as the progression of PKD. In the current study, we examined the role of GLIS3 in the regulation of eicosanoid gene expression and metabolism during this period of kidney development. Transcriptome analysis showed that several eicosanoid metabolic genes are temporally regulated with the expression of some genes decreasing (lipoxygenase and cyclooxygenase arm) and others increasing (the cytochrome P450 pathways), suggesting that these changes are part of part of normal kidney maturation. Many of these temporal changes in eicosanoid gene expression are suppressed in GLIS3-deficient kidneys, consistent with our hypothesis that loss of GLIS3 function inhibits postnatal kidney maturation. Cistrome analyses revealed that several of these eicosanoid genes are directly regulated by GLIS3 and in coordination with hepatocyte nuclear factor 1 beta (HNF1B). Additionally, LC-MS-based eicosanoid metabolomics showed increased levels of PGD₂, PGE₂, TXB₂, and LTB₄ in PND28 GLIS3-deficient polycystic kidneys, consistent with elevated mRNA expression of Ptgs1/2, Alox5ap, Lta4h, and Tbxas1. The increased urinary excretion of PGE₂ and its metabolite PGEM in GLIS3-deficient mice correlates with increased renal production and metabolism of PGE₂ and higher Slco2a1 and Hpgd mRNA expression. Elevated levels of these eicosanoid metabolites might contribute to cystogenesis, altered osmoregulation, inflammation, and fibrosis in GLIS3-deficient kidneys.