Urea and NaCl regulate UT-A1 urea transporter in opposing directions via TonEBP pathway during osmotic diuresis

Abstract

Sands JM, Kim D. Urea and NaCl regulate UT-A1 urea transporter in opposing directions via TonEBP pathway during osmotic diuresis. Am J Physiol Renal Physiol 296: F67-F77, 2009. First published October 22, 2008 doi:10.1152/ajprenal.00143.2008.-In our previous studies of varying osmotic diuresis, UT-A1 urea transporter increased when urine and inner medullary (IM) interstitial urea concentration decreased. The purposes of this study were to examine 1) whether IM interstitial tonicity changes with different urine urea concentrations during osmotic dieresis and 2) whether the same result occurs even if the total urinary solute is decreased. Rats were fed a 4% high-salt diet (HSD) or a 5% high-urea diet (HUD) for 2 wk and compared with the control rats fed a regular diet containing 1% NaCl. The urine urea concentration decreased in HSD but increased in HUD. In the IM, UT-A1 and UT-A3 urea transporters, CLC-K1 chloride channel, and tonicity-enhanced binding protein (TonEBP) transcription factor were all increased in HSD and decreased in HUD. Next, rats were fed an 8% low-protein diet (LPD) or a 0.4% low-salt diet (LSD) to decrease the total urinary solute. Urine urea concentration significantly decreased in LPD but significantly increased in LSD. Rats fed the LPD had increased UT-A1 and UT-A3 in the IM base but decreased in the IM tip, resulting in impaired urine concentrating ability. The LSD rats had decreased UT-A1 and UT-A3 in both portions of the IM. CLC-K1 and TonEBP were unchanged by LPD or LSD. We conclude that changes in CLC-K1, UT-A1, UT-A3, and TonEBP play important roles in the renal response to osmotic diuresis in an attempt to minimize changes in plasma osmolality and maintain water homeostasis.UT-A3 urea transporter; CLC-K1 chloride channel; TonEBP transcription factor THE UT-A1 UREA TRANSPORTER plays a key role in urine concentration in mammals (21). In our previous studies, SpragueDawley rats made diabetic with streptozotocin had a great increase in UT-A1 abundance in both inner medullary (IM) base and tip to conserve water despite the ongoing osmotic diuresis (2, 12, 13). In contrast, diabetic Brattleboro rats (which lack vasopressin) did not increase UT-A1 protein abundance, and vasopressin-treated diabetic Brattleboro rats increased UT-A1 protein abundance more than nondiabetic vasopressintreated Brattleboros (14). This suggests that vasopressin and another factor (or factors) work together to increase UT-A1 abundance.Rats with NaCl diuresis induced by feeding of a high-salt diet also had a significant increase in UT-A1 abundance in both portions of the IM. However, rats with urea diuresis induced by feeding of urea did not increase UT-A1 abundance in either portion of IM, regardless of the severity of the osmotic diuresis (12). Rats with diabetes or NaCl diuresis have relatively decreased urea in the total urinary solute since the excretion of other solutes (glucose or NaCl) is increased, whereas rats fed a high-protein or -urea diet have an increase of urea in the total urinary solute, suggestin...

In-vivo administration of CLC-K kidney chloride channels inhibitors increases water diuresis in rats

“…These findings are consistent with a previous study reporting a down-regulation of ClC-K1 after a 6-day furosemide treatment [39]. It is well known that ClC-K1 gene belongs to the tonicity responsive genes, that is genes encoding renal salt-reabsorbing channels and transporters regulated at the transcriptional level by the salt load [26,37,40]. The transcription factor tonicity-responsive enhancer binding protein (TonEBP) appears to be a key component of hypertonicity signaling being its expression in the renal medulla stimulated by the interstitial tonicity [58].…”

“…Thus, we can speculate that the decrease of ClC-K1 expression in our furosemide-treated animals may be explained by hypotonicity-induced TonEBP-mediated down-regulation, since the furosemide-induced decreased tonicity of inner medulla caused a decreased abundance of TonEBP and finally a decreased TonEBP-mediated transcription of ClC-K1. Therefore, the present results clearly indicate that ClC-K1 might also mediate part of the acute diuretic effect of furosemide and that, importantly, the responsiveness to salt loss depletion of ClC-K1 gene takes place not only after days of drug treatment [39,40], but already within hours post acute dosing. According with previous studies [37,38], ClC-K2 mRNA levels were unaffected by furosemide treatment in each kidney zone.…”

“…The transcription factor tonicity-responsive enhancer binding protein (TonEBP) appears to be a key component of hypertonicity signaling being its expression in the renal medulla stimulated by the interstitial tonicity [58]. Together with urea transporters, ClC-K1 is a transcriptional target of TonEBP [40]. Thus, we can speculate that the decrease of ClC-K1 expression in our furosemide-treated animals may be explained by hypotonicity-induced TonEBP-mediated down-regulation, since the furosemide-induced decreased tonicity of inner medulla caused a decreased abundance of TonEBP and finally a decreased TonEBP-mediated transcription of ClC-K1.…”

“…Regulation of CLC-K expression at the mRNA level may depend on salt load and hydration state [37][38][39][40]: thus we next explored whether acute in-vivo administration of CLC-K inhibitors may affect the expression of these chloride channels.…”

Cyclosporin-A Induced Toxicity in Rat Renal Collecting Duct Cells: Interference with Enhanced Hypertonicity Induced Apoptosis

“…urea) have distinct intracellular effects, specific mechanisms provide adaptations to either increased NaCl or urea concentrations [6,29]. Our data support the idea of crosstalk between adaptation to elevated urea and elevated NaCl (Fig.…”