Regulation of Urea Transporters by Tonicity-responsive Enhancer Binding Protein

Abstract

Urea accumulation in the renal inner medulla plays a key role in the maintenance of maximal urinary concentrating ability. Urea transport in the kidney is mediated by transporter proteins that include renal urea transporter (UT-A) and erythrocyte urea transporter (UT-B). UT-A1 and UT-A2 are produced from the same gene. There is an active tonicity-responsive enhancer (TonE) in the promoter of UT-A1, and the UT-A1 promoter is stimulated by hypertonicity via tonicity-responsive enhancer binding protein (TonEBP). The downregulation of UT-A2 raises the possibility that TonEBP also regulates its promoter. There is some evidence that TonEBP regulates expression of UT-A in vivo; (1) during the renal development of the urinary concentrating ability, expression of TonEBP precedes that of UT-A1; (2) in transgenic mice expressing a dominant negative form of TonEBP, expression of UT-A1 and UT-A2 is severely impaired; (3) in treatment with cyclosporine A, TonEBP was significantly downregulated after 28 days. This downregulation involves mRNA levels of UT-A2; (4) in hypokalemic animals, downregulation of TonEBP contributed to the down regulation of UT-A in the inner medulla. These data support that TonEBP directly contributes to the urinary concentration and renal urea recycling by the regulation of urea transporters.

Keywords: Tonicity-responsive enhancer binding protein; Urea transporters; Urine concentration.

Fig. 1

Renal physiology of TonEBP. NKCC2 and NCC drive accumulation of salt in the medullary interstitium and the medullary ray of the cortex, respectively. The resulting hypertonicity stimulates TonEBP. Stimulation of SMIT, BGT1, AR, and TauT leads to cellular accumulation of organic osmolytes and protection from the deleterious effects of hypertonicity. Stimulation of UT-A1 and UT-A2 leads to accumulation of urea in the renal medulla, which provides the majority of osmotic gradient for urinaryconcentration. Although not directly demonstrated, stimulation of AQP2 would contribute further to urinary concentration by facilitating reabsorption of water. The high expression of HSP70 protects cells from the harmful effects of high urea in the renal medulla. [Figure obtained from Jeon US et al. Acta Physiol (Oxf) 187:241-247, 2006]

Fig. 2

Light micrographs of 50-µm thick Vibratome sections from kidneys of 7 (A)-, 14 (B)-, and 21-day-old (C) rat pups illustrating UT-A immunostaining. A: UT-A immunoreactivity was present only in the IMCD in the terminal half of renal papilla (arrowhead) and in the DTL of immature loops of Henle (open arrow) located at the border between outer medulla and inner medulla at 7 days after birth. B: UT-A immunoreactivity appeared in the terminal part of DTL of short loop of Henle (arrow) in the inner stripe of outer medulla at 14 days after birth. Note the strong immunoreactivity in the DTL of long loop of Henle (open arrow) and IMCD (arrowhead). C: in 21-day old pups, immunoreactivity for UT-A was increased in the DTL of short loop of Henle (arrow). Incontrast, the intensity of immunoreactivity in the long loop DTL (open arrow) was markedly decreased. [From Kim YH, Kim DU, Han KH, Jung JY et al.: Am J Physiol Renal Physiol 282:F530-F540, 2002]

Fig. 3

Diagrams summarizing the expression profiles of NKCC2, TonEBP, AR, and UT-A in developing mouse and rat kidneys. Nuclear shift of TonEBP after birth is indicated. VE, vascular endothelial cells; CD, collecting duct cells; lDTL, long-looped descending thin limb; sDTL, shortlooped descending thin limb. [Diagram obtained from Lee HW et al. Am J Physiol Renal Physiol 292:F269-F277, 2007]