Tonicity-dependent induction of Sgk1 expression has a potential role in dehydration-induced natriuresis in rodents

Abstract

In various mammalian species, including humans, water restriction leads to an acute increase in urinary sodium excretion. This process, known as dehydration natriuresis, helps prevent further accentuation of hypernatremia and the accompanying rise in extracellular tonicity. Serum-and glucocorticoid-inducible kinase (Sgk1), which is expressed in the renal medulla, is regulated by extracellular tonicity. However, the mechanism of its regulation and the physiological role of hypertonicity-induced SGK1 gene expression remain unclear. Here, we identified a tonicity-responsive enhancer (TonE) upstream of the rat Sgk1 transcriptional start site. The transcription factor NFAT5 associated with TonE in a tonicity-dependent fashion in cultured rat renal medullary cells, and selective blockade of NFAT5 activity resulted in suppression of the osmotic induction of the Sgk1 promoter. In vivo, water restriction of rats or mice led to increased urine osmolality, increased Sgk1 expression, increased expression of the type A natriuretic peptide receptor (NPR-A), and dehydration natriuresis. In cultured rat renal medullary cells, siRNA-mediated Sgk1 knockdown blocked the osmotic induction of natriuretic peptide receptor 1 (Npr1) gene expression. Furthermore, Npr1 -/-mice were resistant to dehydration natriuresis, which suggests that Sgk1-dependent activation of the NPR-A pathway may contribute to this response. Collectively, these findings define a specific mechanistic pathway for the osmotic regulation of Sgk1 gene expression and suggest that Sgk1 may play an important role in promoting the physiological response of the kidney to elevations in extracellular tonicity. IntroductionPersistent hypertonicity, typically reflecting a high extracellular sodium concentration, stresses mammalian cells due to the ensuing osmotic efflux of water that shrinks the cells and concentrates their contents. Under most conditions, the concentration of extracellular sodium in mammals is controlled primarily through regulation of water metabolism. As extracellular sodium and plasma tonicity rise, the thirst mechanism is activated, and secretion of the neurohypophyseal hormone vasopressin into plasma increases. Vasopressin binds to its cognate receptors in the collecting duct of the kidney, resulting in increased water retention.Following short-term water restriction, several mammals demonstrate an acute increase in urinary sodium excretion that is independent of changes in water metabolism. This response, termed dehydration natriuresis (1-11), plays an important role in preventing further accentuation of hypernatremia and the accompanying rise in extracellular tonicity. A similar natriuresis is seen following infusion of hypertonic saline (12). Investigations to date have suggested a role for central versus peripheral osmoreceptors and blood-borne versus neural effectors in contributing to dehydration-induced natriuresis; however, the precise mechanism(s) underlying this natriuresis remains undefined.

Rac1/osmosensing scaffold for MEKK3 contributes via phospholipase C-γ1 to activation of the osmoprotective transcription factor NFAT5

“…However, although MKK6 is involved in high NaCl-induced increase of TonEBP/OREBP transcriptional activity, MKK3 is not. Dominant-negative MKK6 reduces high NaCl-induced TonEBP/OREBP transcriptional activity in mouse inner medullary collecting duct cells (30) as siRNA does against MKK6 in HEK293 cells (Fig. 3B).…”

Rehydration with soft drink-like beverages exacerbates dehydration and worsens dehydration-associated renal injury

“…Although volume contraction is known to cause a prerenal state with a decrease in fractional excretion of sodium, dehydration-induced hyperosmolarity can cause a mild natriuresis (known as dehydration natriuresis) (13). The signaling mechanisms (Sgk1 and TonEBP) involved in causing dehydration-induced natriuresis are the same as those known to stimulate the aldose reductase-fructokinase pathway and thus may account for the potentiation of this mechanism with the FG solutions (13,43). It was also observed a significant increase in urinary urea excretion in FG-rehydrated animals.…”

How do kinases contribute to tonicity-dependent regulation of the transcription factor NFAT5?

“…Water restriction induces an increase of urinary excretion of sodium to prevent hypernatremia and rise in extracellular tonicity. In the primary rat renal medullary cells, NFAT5 is necessary for hypertonicityinduced increase of serum-and glucocorticoid-inducible kinase-dependent expression of the type A natriuretic peptide receptor [13] . This cascade might be a mechanism for dehydration-induced natriuresis [13] .…”

“…In the primary rat renal medullary cells, NFAT5 is necessary for hypertonicityinduced increase of serum-and glucocorticoid-inducible kinase-dependent expression of the type A natriuretic peptide receptor [13] . This cascade might be a mechanism for dehydration-induced natriuresis [13] . Besides activation by hypertonicity, NFAT5 is also activated by hypoxia [14,15] .…”

“…This paradox can be explained by the interpretation that inhibition of the positive effect of p38α by SB203580, a dominant negative mutant [54] or its siRNAs [51] unmasks an inhibitory effect of p38δ, whereas the dominant negative mutant of MKK3 [50,65] and MKP-1 [51] reduce both p38α and p38δ activities, therefore, causing no significant change in NFAT5 activity [51,64] . Based on this theory, it is not surprising that another p38 upstream kinase MKK6 [13,66] and the MKK3 and MKK6 upstream kinase MEKK3 [67] have been demonstrated to contribute to tonicity-dependent activation of NFAT5, because although both MKK3 and MKK6 activate p38α under hypertonicity [68,69] , MKK3 strongly activates p38δ, whereas MKK6 does not [70] . Although p38 is the most studied MAPKs in the (1) PKA exists as a heterotetramer composed of two regulatory subunits and two catalytic subunits.…”