Transcriptional regulation of urate transportosome member SLC2A9 by nuclear receptor HNF4α

Katharina Prestin, Stephanie Wolf, Rico Feldtmann, Janine Hussner, Ingrid Geissler, Christian Rimmbach, Heyo K Kroemer, Uwe Zimmermann, Henriette E Meyer zu Schwabedissen

Renal tubular handling of urate is realized by a network of uptake and efflux transporters including members of drug transporter families such as solute carrier proteins, and ATP-binding cassette transporters. The solute carrier family 2, member 9 (SLC2A9) is one key factor of this so called "urate transportosome". The aim of our study was to understand the transcriptional regulation of SLC2A9 and to test whether identified factors might contribute to a coordinated transcriptional regulation of the transporters involved in urate handling. In silico analysis, and cell based reportergene assays identified an HNF4α (hepatocyte nuclear factor 4 alpha) binding site in the promoter of SLC2A9 isoform 1, whose activity was enhanced by transient HNF4α overexpression, while mutation of the binding site diminished activation. HNF4α overexpression induced endogenous SLC2A9 expression in vitro. The in vivo role of HNF4α in modulation of renal SLC2A9 gene expression was supported by findings of quantitative real-time PCR analyses and chromatin immunoprecipitation assay. Indeed, mRNA-expression of SLC2A9 and HNF4a in human kidney samples was significantly correlated. We also show that in renal clear cell carcinoma down-regulation of HNF4α mRNA and protein expression is associated with a significant decline in expression of the transporter. Taken together, our data suggest that the nuclear receptor family member HNF4α contributes to the transcriptional regulation of SLC2A9 isoform 1. Since HNF4α has previously been assumed to be a modulator of several urate transporters, our findings support the notion that there could be a transcriptional network providing synchronized regulation of the urate transportosome.