c/ebpdelta Null mouse as a model for the double knock-out of slc5a8 and slc5a12 in kidney.

slc5a8 and slc5a12 represent the high affinity and low affinity Na+/lactate co-transporters, respectively, in the kidney. Here we show that these transporters are expressed in the apical membrane of the proximal tubular cells in mouse kidney, indicating that these transporters are likely to mediate the first step in the renal reabsorption of lactate. Interestingly, the renal expression of both transporters is almost completely ablated in mice homozygous for the deletion of the transcription factor c/ebpdelta. This effect is tissue-specific since the expression of the transporters is not affected in non-renal tissues. The functional role of C/EBPdelta in the expression of SLC5A8 and SLC5A12 is demonstrable in HEK293 cells in reporter assays using gene-specific promoters. The ablation of the transporters in the kidney is accompanied by a marked increase in urinary excretion of lactate as well as a decrease in blood levels of lactate in c/ebpdelta-/- mice. These data provide evidence for an obligatory role for slc5a8 and slc5a12 in the renal absorption of lactate. In addition, we show that urinary excretion of urate is significantly elevated in c/ebpdelta-/- mice even though the expression of URAT1, the transporter responsible for the apical membrane uptake of urate in renal proximal tubule, is not altered. These data provide in vivo evidence for the functional coupling between lactate reabsorption and urate reabsorption in the kidney. Thus, the fortuitous double knock-out of slc5a8 and slc5a12 in kidney in c/ebpdelta-/- mice reveals the physiologic role of these transporters in the renal handling of lactate and urate.