A schematic model of Vpr suppression of <i>SLC12A3</i> transcription activity in the distal convoluted tubule.

(A) In the absence of Vpr, aldosterone binds MR in the cytoplasm. The activated MR translocates to the nucleus, where it binds the mineralocorticoid response element (MRE) in genomic DNA. This complex, together with SP1 and other transcription factor(s) and other co-regulator(s), activates the transcription initiation complex and thereby promotes SLC12A3 gene transcription and NCC protein translation. Although both MR (aldosterone) and GR (cortisol, corticosterone etc.) hormones potentially bind to MRE, the presence of 11βHSD2 in the DCT, especially DCT2, converts cortisol (humans)/corticosterone (rodents) to cortisone, which facilitates MR binding to MRE. (B) Vpr, binding either MR or SP1 and other transcription factors, abrogates the interaction of MR and MRE and thus prevents SLC12A3 transcription and translation. This reduces the abundance of NCC in the apical membranes of distal convoluted tubules. Considering that plasma aldosterone levels in Tg mice were similar to those of WT mice, and aldosterone concentrations were increased by salt depletion in both groups, Vpr did not impair aldosterone synthesis and regulation system in Tg mice. Of note, MREs can be located within intron or other regions of the gene, although it is illustrated here in the promoter region of SLC12A3.