Osmolytes and Cell‐Volume Regulation: Physiological and Evolutionary Principles

Somero, George N.; Yancey, Paul H.

doi:10.1002/cphy.cp140110

Cited by 63 publications

(66 citation statements)

References 199 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The blots were stripped and rehybridized for GAPDH to demonstrate comparable RNA loading Fig. 5A tions, which are easily reached in the papilla of the concentrating kidney, inhibit enzyme functions, have denaturing effects on nucleic acids and other cellular macromolecules, and promote apoptosis in inner medullary collecting duct cells [6,13,21]. In agreement with a recent report by Sheikh-Hamad and coworkers [20], the highly specific p38 kinase inhibitor SB203580, added at a concentration of 100 µM to the hypertonic medium, significantly reduced HSP72 mRNA expression.…”

Section: Discussionmentioning

confidence: 99%

“…Inner medullary urea concentrations may reach values at which protein function and cell viability are compromised [21]. It is well established that the cells in the renal medulla accumulate low-molecular-weight organic osmolytes in response to hypertonic stress, thus maintaining cell volume and osmotic equilibrium with the high extracellular NaCl concentrations [2,21].…”

Section: Introductionmentioning

confidence: 99%

“…It is well established that the cells in the renal medulla accumulate low-molecular-weight organic osmolytes in response to hypertonic stress, thus maintaining cell volume and osmotic equilibrium with the high extracellular NaCl concentrations [2,21]. Amongst these osmolytes, the trimethylamines glycerophosphorylcholine (GPC) and betaine are assumed to counteract some of the deleterious effects of high urea concentrations on protein function [21]. However, in addition to enhancing intracellular osmolyte accumulation, hypertonic stress also activates the production of specific heat shock proteins (HSPs).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of NaCl-induced heat shock protein 72 expression renders MDCK cells susceptible to high urea concentrations

Neuhofer¹,

Müller²,

Burger‐Kentischer³

et al. 1999

Pfl�gers Archiv European Journal of Physiology

View full text Add to dashboard Cite

Exposure of Madin-Darby canine kidney (MDCK) cells to elevated extracellular NaCl concentrations is associated with increased heat shock protein 72 (HSP72) expression and improved survival of these pretreated cells upon exposure to an additional 600 mM urea in the medium. To establish a causal relationship between HSP72 expression and cell protection against high urea concentrations, two approaches to inhibit NaCl-induced HSP72 synthesis prior to exposure to 600 mM urea were employed. First, the highly specific p38 kinase inhibitor SB203580 was added (100 microM) to the hypertonic medium (600 mosm/kg H2O by NaCl addition, 2 days of exposure), which significantly reduced HSP72 mRNA abundance and HSP72 content. Survival of these cells after a 24-h urea treatment (600 mM) was markedly curtailed compared with appropriate controls. Second, a pcDNA3-based construct, containing 322 bases of the HSP72 open reading frame in antisense orientation and the geneticine resistance gene, was transfected into MDCK cells. Clones with strong inhibition of HSP72 synthesis and others which express the protein at normal levels (comparable to nontransfected MDCK cells) after heat shock treatment or hypertonic stress were established. When these transformants were subjected to hypertonic stress for 2 days prior to exposure to an additional 600 mM urea for 24 h, cell survival was significantly reduced in those clones in which HSP72 expression was strongly inhibited. These results provide further evidence for the protective function of HSP72 against high urea concentrations in renal epithelial cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of NaCl-induced heat shock protein 72 expression renders MDCK cells susceptible to high urea concentrations

Neuhofer¹,

Müller²,

Burger‐Kentischer³

et al. 1999

Pfl�gers Archiv European Journal of Physiology

View full text Add to dashboard Cite

show abstract

“…In renomedullary cells, osmotic equilibrium with these elevated extracellular NaCl concentrations is achieved primarily by intracellular accumulation of small organic solutes ("organic osmolytes") [8,42]. In contrast to inorganic electrolytes (Na + , Cl -, K + ), organic osmolytes do not severely impair cell function even at high concentrations and are thus termed "compatible" osmolytes [122]. In the mammalian kidney, these osmolytes include the trimethylamines betaine and glycerophosphorylcholine (GPC), the polyols sorbitol and myo-inositol and, quantitatively less important, free amino acids and their derivatives [8,9,42,77].…”

Section: Introductionmentioning

confidence: 99%

Cellular response to osmotic stress in the renal medulla

Beck¹,

Burger‐Kentischer²,

Müller³

1998

Pfl�gers Archiv European Journal of Physiology

View full text Add to dashboard Cite

Cells of the renal medulla, which are exposed under normal physiological conditions to widely fluctuating extracellular solute concentrations, respond to hypertonic stress by accumulating the organic osmolytes glycerophosphorylcholine (GPC), betaine, myo-inositol, sorbitol and free amino acids. Increased intracellular contents of these osmolytes are achieved by a combination of increased uptake (myo-inositol and betaine) and synthesis (sorbitol, possibly GPC), decreased degradation (GPC) and reduced osmolyte release. In the medulla of the concentrating kidney, accumulation of organic osmolytes, which do not perturb cell function even at high concentrations, allows the maintenance of "normal" intracellular concentrations of inorganic electrolytes. Adaptation to decreasing extracellular solute concentrations, e.g. diuresis, is achieved primarily by activation of pathways allowing the efflux of organic osmolytes, and secondarily by inactivation of production (sorbitol) and uptake (betaine, myo-inositol) and stimulation of degradation (GPC). Apart from modulation of the osmolyte content, osmolality-dependent reorganization of the cytoskeleton and expression of specific stress proteins (heat shock proteins) may be further, as yet poorly characterized, components of the regulatory systems involved in the adaptation of medullary cells to osmotic stress.

show abstract

“…Such protective responses are necessary because osmotic stress alters cell volume, the concentration and stability of proteins, and the rate of biochemical reactions (1). Proteins are protected from osmotic stress by molecular chaperones and compatible organic osmolytes (2,3).…”

mentioning

confidence: 99%

Hyperosmolality in the form of elevated NaCl but not urea causes DNA damage in murine kidney cells

Kültz

Chakravarty

2001

Proc. Natl. Acad. Sci. U.S.A.

175

119

View full text Add to dashboard Cite

This study demonstrates, by using neutral comet assay and pulsed field gel electrophoresis, that hyperosmotic stress causes DNA damage in the form of double strand breaks (dsb). Different solutes increase the rate of DNA dsb to different degrees at identical strengths of hyperosmolality. Hyperosmolality in the form of elevated NaCl (HNa) is most potent in this regard, whereas hyperosmolality in the form of elevated urea (HU) does not cause DNA dsb. The amount of DNA dsb increases significantly as early as 15 min after the onset of HNa. By using neutral comet and DNA ladder assays, we show that this rapid induction of DNA damage is not attributable to apoptosis. We demonstrate that renal inner medullary cells are able to efficiently repair hyperosmotic DNA damage within 48 h after exposure to hyperosmolality. DNA repair correlates with cell survival and is repressed by 25 M LY294002, an inhibitor of DNA-activated protein kinases. These results strongly suggest that the hyperosmotic stress resistance of renal inner medullary cells is based not only on adaptations that protect cellular proteins from osmotic damage but, in addition, on adaptations that compensate DNA damage and maintain genomic integrity. C ells adapt to osmotic stress by cell volume regulation and protection of protein structure, activity, and metabolism to maintain proper cell function. Such protective responses are necessary because osmotic stress alters cell volume, the concentration and stability of proteins, and the rate of biochemical reactions (1). Proteins are protected from osmotic stress by molecular chaperones and compatible organic osmolytes (2, 3). We recently showed that mouse renal inner medullary collecting duct (mIMCD3) cells respond to hyperosmotic stress by induction of cell cycle arrest, the tumor suppressor p53, and the growth arrest and DNA damage inducible proteins GADD45 and GADD153 (4,5). These responses are known hallmarks of signaling pathways that counteract DNA damage in mammalian cells (6, 7). DNA damage is defined as an alteration of DNA structure capable of causing cellular injury and reduction of viability or reproductive fitness of the organism (8). Thus, an induction of DNA repair pathways may be required to confer the high osmotic stress tolerance that is characteristic of renal inner medullary cells. However, in contrast to the wealth of knowledge about osmotic effects on cell volume and protein stability and function, little is known about the consequences of osmotic stress on DNA integrity in mammalian cells. Studies on several mammalian cell lines, including CHO cells (9), PAP-HT25 cells (10), human peripheral lymphocytes (11), and V79 cells (12), indicate that osmotic stress can lead to chromosomal aberrations. Such aberrations may be the consequence of an increased frequency of DNA double strand breaks (dsb) or result from an inhibition of constitutive DNA-repair mechanisms. Hyperosmotic stress inhibits inducible DNA repair pathways that are activated in response to ionizing radiation in some mammalian cell...

show abstract

Osmolytes and Cell‐Volume Regulation: Physiological and Evolutionary Principles

Cited by 63 publications

References 199 publications

Inhibition of NaCl-induced heat shock protein 72 expression renders MDCK cells susceptible to high urea concentrations

Inhibition of NaCl-induced heat shock protein 72 expression renders MDCK cells susceptible to high urea concentrations

Cellular response to osmotic stress in the renal medulla

Hyperosmolality in the form of elevated NaCl but not urea causes DNA damage in murine kidney cells

Contact Info

Product

Resources

About