scholarly journals The Adaptation Mechanism to Hypertonic Stress in the Renal Medulla-The Function of TonEBP Transcriptional Activator

2004 ◽  
Vol 2 (1) ◽  
pp. 45
Author(s):  
Gi Yeong Na
Physiology ◽  
2009 ◽  
Vol 24 (3) ◽  
pp. 186-191 ◽  
Author(s):  
Min Seong Kwon ◽  
Sun Woo Lim ◽  
H. Moo Kwon

The interstitium of the renal medulla is hypertonic, imposing deleterious effects on local cells. At the same time, the hypertonicity provides osmotic gradient for water reabsorption and is a local signal for tissue-specific gene expression and differentiation of the renal medulla, which is a critical organ for water homeostasis.


1992 ◽  
Vol 262 (5) ◽  
pp. F849-F856 ◽  
Author(s):  
F. X. Beck ◽  
M. Schmolke ◽  
W. G. Guder ◽  
A. Dorge ◽  
K. Thurau

The effect of acute changes in extracellular tonicity on cell electrolyte concentrations at the renal papillary tip and on organic osmolytes in different kidney zones was studied using electron microprobe analysis and high-performance liquid chromatography in four groups of rats: controls, 1- or 4-h water diuresis, and 4-h water diuresis followed by 30-min deamino-[Cys1,D-Arg8]vasopressin (ddAVP). The sum of the papillary interstitial concentrations of Na, K, and Cl was reduced from 981 mmol/kg wet wt in controls to 318 mmol/kg wet wt after 4-h diuresis and increased after ddAVP to 840 mmol/kg wet wt. In papillary collecting ducts intracellular electrolytes fell from 225 to 156 mmol/kg wet wt after 4-h diuresis and rose to 268 mmol/kg wet wt (significantly higher than control) after ddAVP. Organic osmolytes [sum of glycerophosphorylcholine (GPC), betaine, myo-inositol, and sorbitol] at the papillary tip decreased from 2,018 (control) to 1,037 mmol/kg protein after 4-h diuresis and did not increase after ddAVP. After ddAVP, cell P concentration, an index of cell GPC concentration, increased, indicating cell shrinkage. GPC concentration increased, indicating cell shrinkage. The results suggest that the concentrations of all osmoeffectors in papillary cells initially increase due to cell shrinkage in response to hypertonic stress. The higher intracellular ionic strength may be a signal for modulation of transport and metabolism of organic osmolytes.


2011 ◽  
Vol 300 (3) ◽  
pp. F707-F715 ◽  
Author(s):  
Sang Do Lee ◽  
Soo Youn Choi ◽  
Sun Woo Lim ◽  
S. Todd Lamitina ◽  
Steffan N. Ho ◽  
...  

TonEBP (tonicity-responsive enhancer binding protein) is a transcription factor that promotes cellular accumulation of organic osmolytes in the hypertonic renal medulla by stimulating expression of its target genes. Genetically modified animals with deficient TonEBP activity in the kidney suffer from severe medullary atrophy in association with cell death, demonstrating that TonEBP is essential for the survival of the renal medullary cells. Using both TonEBP knockout cells and RNA interference of TonEBP, we found that TonEBP promoted cellular adaptation to hypertonic stress. Microarray analyses revealed that the genetic response to hypertonicity was dominated by TonEBP in that expression of totally different sets of genes was increased by hypertonicity in those cells with TonEBP vs. those without TonEBP activity. Of over 100 potentially new TonEBP-regulated genes, we selected seven for further analyses and found that their expressions were all dependent on TonEBP. RNA interference experiments showed that some of these genes, asporin, insulin-like growth factor-binding protein-5 and -7, and an extracellular lysophospholipase D, plus heat shock protein 70, a known TonEBP target gene, contributed to the adaptation to hypertonicity without promoting organic osmolyte accumulation. We conclude that TonEBP stimulates multiple cellular pathways for adaptation to hypertonic stress in addition to organic osmolyte accumulation.


2011 ◽  
Vol 300 (3) ◽  
pp. C692-C696 ◽  
Author(s):  
Sang Do Lee ◽  
Soo Youn Choi ◽  
H. Moo Kwon

During antidiuresis with elevated vasopressin, urea accumulates in the renal medulla to very high concentrations, imposing considerable cellular stress. How local cells cope with urea stress is relevant to the whole kidney because the renal medulla is the major site of residence for the renal stem cells. Previous studies showed that renal cells were incapable of preconditioning in moderate urea concentrations to enhance resistance to urea stress. Instead, preconditioning in moderately high salinity (moderate hypertonicity) has been shown to promote resistance to urea stress due to the induction of the molecular chaperone heat shock protein 70 (Hsp70), which is mediated by the transcription factor tonicity-responsive enhancer binding protein (TonEBP). Here we report that cell lines derived from the kidney and fibroblasts display enhanced resistance to urea stress after pretreatment in moderate, nonstressful concentrations of urea. Using TonEBP knockdown and immunoblot analyses, we demonstrate that TonEBP and Hsp70 are dispensable for the increased resistance to urea stress. These data suggest that cells in the renal medulla are capable of overcoming urea stress by activating distinct cellular pathways.


2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Christopher R. Day ◽  
Sashana S. Gordon ◽  
Cherissa L. Vaughn ◽  
Stephen A. Kempson

One response to hypertonic stress in the renal medulla and MDCK cells is the upregulation of betaine transporter (BGT1) synthesis, followed by trafficking to the plasma membrane (PM) and an increase in betaine transport. Upregulation of BGT1 was enhanced by inhibitors of phosphatases PP1 and PP2A and was attenuated by inhibitors of protein kinase C, suggesting an important role for phosphorylation reactions. This was tested using mutants of BGT1 tagged with EGFP. The PM trafficking motifs of BGT1 reside near the C terminus, and truncation at lysine560 resulted in a protein that remained intracellular during hypertonic stress. This K560Δ mutant colocalized with endoplasmic reticulum (ER). Substitution of alanine at Thr40, a putative phosphorylation site, also prevented trafficking to the PM during hypertonic stress. Live-cell imaging showed that T40A was not retained in the ER and colocalized with markers for Golgi and endosomes. In contrast, substitution of aspartate or glutamate at Thr40, to mimic phosphorylation, restored normal trafficking to the PM. HEK293 cells transfected with K560Δ or T40A mutants had 10% of the GABA transport activity of native BGT1, but normal transport activity was restored in cells expressing T40E. Normal BGT1 trafficking likely requires phosphorylation at Thr40 in addition to C-terminal motifs.


2011 ◽  
Vol 301 (6) ◽  
pp. F1202-F1207 ◽  
Author(s):  
Qi Cai ◽  
Heddwen L. Brooks

The phosphorylation of the α-subunit of the eukaryotic translation initiation factor 2 (eIF2α) occurs under many stress conditions in mammalian cells and is mediated by one of four eIF2α kinases: PERK, PKR, GCN2, and HRI. Cells of the renal medulla are regularly exposed to fluctuating concentrations of urea and sodium, the extracellular solutes responsible for the high osmolality in the renal medulla, and thus the kidneys ability to concentrate the urine in times of dehydration. Urea stress is known to initiate molecular responses that diverge from those seen in response to hypertonic stress (NaCl). We show that urea-inducible GCN2 activation initiates the phosphorylation of eIF2α and the downstream increase of activating transcription factor 3 (ATF3). Loss of GCN2 sensitized cells to urea stress, increasing the expression of activated caspase-3 and decreasing cell survival. Loss of GCN2 ablated urea-induced phosphorylation of eIF2α and reduced the expression of ATF3.


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