Hypertonicity and TonEBP promote development of the renal concentrating system

Abstract

DESPITE SEVERE HYPEROSMOTIC stress imposed by NaCl and urea on cells of the renal medulla, the elevated and highly variable osmolality in this part of the kidney is necessary for proper function of the urinary concentrating mechanism. This mechanism develops only after birth, and newborn rats are incapable of producing concentrated urine (13). Depending on hydration state, renal medullary osmolality of adult rats ranges from 500 to Ͼ2,500 mosmol/kgH 2 O as a result of elevated salt and urea concentrations. Although increases in salt and urea both lead to hyperosmolality, only increased salt concentration causes hypertonicity (leading to cell shrinkage). The reason for this difference between salt and urea is the high membrane permeability of urea, which is mostly comparable to that of water. Consequently, urea and salt have different effects on kidney cells. In this issue of AJP-Renal Physiology, Han and coworkers (6) show that hypertonicity in the renal medulla represents an important signal for medullary differentiation and development of the urinary concentrating mechanism.Over the years, remarkable progress has been made in our understanding of how kidney cells adapt to the stress of hypertonicity. Cellular accumulation of organic osmolytes such as inositol, betaine, and sorbitol represents a central feature of adaptation to hypertonic stress. Organic osmolytes are compatible with cell function and protect renal cells from deleterious effects of hypertonicity by lowering intracellular ionic strength (2). The transcription factor tonicity-responsive enhancer binding protein (TonEBP) plays a key role in the accumulation of organic osmolytes by stimulating gene expression of membrane transporters (sodium-inositol cotransporter and sodium-chloride-betaine cotransporter) and a biosynthetic enzyme (aldose reductase) that catalyzes production of sorbitol from glucose (14). Interestingly, TonEBP also stimulates transcription of genes encoding vasopressin-activated urea transporters (UT-A1 and UT-A3) in inner medullary collecting duct cells, suggesting that TonEBP contributes to urea accumulation in renal medullary interstitium (12). In addition, TonEBP stimulates expression of the heat shock protein HSP70, which in turn protects proteins from the denaturing effects of urea (15). These wide-ranging transcriptional targets delineate TonEBP as a critical element of osmosensory signal transduction in cells of the renal medulla.The article by Han et al. (6) provides insight into how TonEBP contributes to development of urinary concentrating ability by analysis of expression of TonEBP and its target genes in developing rat kidney. TonEBP expression is first detected in the renal medulla at the fetal age of 16 days. It increases slowly through birth until postnatal day 21, when the renal medulla is fully developed and maximal urinary concentrating ability is achieved. Han et al. observe that, in general, expression of TonEBP in the kidney precedes that of its target genes, such as the sodium-inositol cotransporter, aldose ...

Genetic restoration of aldose reductase to the collecting tubules restores maturation of the urine concentrating mechanism

“…This also suggested that AR expression has to precede the initiation of the development of the urine concentrating mechanism, a finding that is consistent with previous AR developmental expression studies (39). As suggested by others (19,24), local hypertonicity and cell shrinkage could be important triggering factors for renal cell apoptosis during kidney development. Indeed, apoptosis was suggested to be part of the mechanism for lengthening of the thin ascending limb and the separation of the inner and outer medulla (19).…”

“…Urine osmolality rises from 300 mosmol/kgH 2 O at birth to nearly 2,000 mosmol/ kgH 2 O by the age of 3 wk (39). The maturation of this mechanism is believed to be developmentally regulated and may be regulated by corticosteroid hormones (37) and/or hypertonicity and the osmoresponsive transcriptional factor tonicity-responsive element binding protein (TonEBP)/osmotic response element binding protein (OREBP) (15,24), the latter being the only known osmotic-responsive transcriptional activator. Loss of TonEBP/OREBP resulted in renal atrophy and lack of tonicity-responsive gene regulation, defective urine concentration, and the development of polyuria and polydipsia (28).…”

TAG synthesis and storage under osmotic stress. A requirement for preserving membrane homeostasis in renal cells

“…However, under physiological conditions, hyperosmolarity induces renal cell differentiation and the maturation of urine concentrating system. Moreover, variation of interstitial osmolality is necessary to concentrate urine in mature kidneys [14,17,33]. Interestingly, both situations require an active lipid metabolism: as a protective mechanism against osmotic stress for preserving membrane structure and as a physiological tool for constructing cell structure and tissue architecture of differentiated cell state.…”

“…to trigger adaptive responses to survive [13,14]. In addition, hyperosmolarity is a main signal for renal tubular cells differentiation [15][16][17]. Former works from our laboratory showed that the renal inner medullary cells possess the most dynamic phospholipid synthesis and membrane turnover among the various kidney zones [18,19].…”

“…Afterwards, cells activate adaptive mechanisms such as accumulation of organic osmolytes and transcription of osmoprotective genes. After 20 h, cells are adapted and activate the transcription of specific genes for renal function or differentiation [14,17,52]. Hence, the kinetic of renal cell adaption and differentiation goes along with the kinetic of glycerolipids synthesis presented herein.…”