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发表于 2009-4-21 12:37 |只看该作者 |倒序浏览 |打印

Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung, and Blood Institute, Department of Health and Human Services, Bethesda, Maryland

ABSTRACT

Renal medullary cells normally are exposed to extraordinarily high interstitial NaCl concentration as part of the urinary concentrating mechanism, yet they survive and function. Acute elevation of NaCl to a moderate level causes transient cell cycle arrest in culture. Higher levels of NaCl, within the range found in the inner medulla, cause apoptosis. Recently, it was surprising to discover that even moderately high levels of NaCl cause DNA double-strand breaks. The DNA breaks persist in cultured cells that are proliferating rapidly after adaptation to high NaCl, and DNA breaks normally are present in the renal inner medulla in vivo. High NaCl inhibits repair of broken DNA both in culture and in vivo, but the DNA is rapidly repaired if the level of NaCl is reduced. The inhibition of DNA repair is associated with suppressed activity of some DNA damage-response proteins like Mre11, Chk1, and H2AX but not that of others, like GADD45, p53, ataxia telangiectasia-mutated kinase (ATM), and Ku86. In this review, we consider possible mechanisms by which the renal cells escape the known dangerous consequences of persistent DNA damage. Furthermore, we consider that the persistent DNA damage may be a sensor of hypertonicity that activates ATM kinase to provide a signal that contributes to protective osmotic regulation.

hypertonicity; renal medulla; apoptosis; cell cycle delay
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BACKGROUND: DNA DAMAGE AND REPAIR1 ?) g* i" u$ Y( E

MANY EXOGENOUS AND ENDOGENOUS stresses damage DNA. Examples include ionizing radiation, UV radiation, chemical carcinogens, reactive oxygen species (ROS), alkylating agents, and more. All cells have DNA damage-response pathways that can repair DNA accurately and prevent accumulation of mutations. This is essential for preventing diseases caused by both genetically transmitted and acquired mutations. The general organization of the DNA damage response is shown in Fig. 1. DNA damage rapidly arrests the cell cycle, and DNA repair, specific to the type of DNA damage, is activated. The cell cycle arrest generally persists until the DNA is repaired. Failure to repair the DNA damage activates apoptosis (programmed cell death), which eliminates potentially malignant cells. Thus DNA is under constant surveillance by the DNA damage-response network, and coordinated activity of all its components is required to ensure genomic stability and to minimize mutations. The exact nature of the response depends on the type and extent of the DNA damage. Not all DNA breaks are pathological. Transient breaks occur during normal DNA replication, transcription, and recombination. These breaks are rapidly repaired by the same players that respond to DNA damage of exogenous origin (66). Therefore, accumulation of DNA damage and/or mutations can occur even in the absence of obvious DNA damaging stress if any of the components of the repair network are compromised. Many severe human diseases are recognized that are linked to mutations in genes encoding proteins that participate in DNA repair and cell cycle control (reviewed in Ref. 52). Furthermore, studies of transgenic mice have identified many genes involved in DNA repair or cell cycle control whose malfunction is lethal (42, 71, 77) or leads to premature aging, due to accelerated accumulation of DNA damage and mutations (15, 30, 52).& |  n* i7 l. B" G9 C9 s

With this as background, recent observations of cells in the renal inner medulla are particularly striking. Renal inner medullary cells contain many DNA breaks in vivo and their DNA repair is defective under normal conditions, yet the cells do not suffer the expected consequences (21, 23). The high osmolality in the renal inner medulla is responsible for the DNA breaks and for inhibition of their repair.) W1 z; U# w. S+ y" l1 d, J
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HYPERTONICITY-INDUCED DNA DAMAGE IN CELL CULTURE AND IN THE RENAL MEDULLA IN VIVO

Realization that high NaCl is genotoxic has evolved over many years (reviewed in Refs. 21, 22, 38, 39). Most recently, acute elevation of NaCl was observed to cause cell cycle arrest (41, 46) and to activate such important responders to DNA damage as GADD45 (41) and p53 (17, 18) (Fig. 2). Acute elevation of osmolality from 300 to 500–600 mosmol/kgH2O by adding NaCl causes DNA breaks in mIMCD3 cells (40). This discovery led to further studies of how cells respond to DNA damage induced by high NaCl. Initially, there is transient arrest at all stages of the cell cycle. Activation of G2/M arrest depends on p38 kinase (20), similar to the response to UV radiation (6). In the presence of high NaCl, overexpression of Gadd45 proteins inhibits mitosis and promotes G2/M arrest (43). G1 arrest depends on p53 (18), as is the case with many other DNA-damaging agents (reviewed in Ref. 24). After several hours, the cells begin proliferating again, despite the continued presence of high NaCl (9, 56). This sequence is very similar to the classic DNA damage response, as depicted in Fig. 1, which led us to assume initially that cell cycle arrest provides time for repair of DNA damage, as is the case following ionizing radiation. However, to our surprise, cells in culture that have adapted to high NaCl, and are proliferating rapidly, still contain numerous DNA breaks (23). Despite the DNA breaks, the adapted cells appear normal and exhibit little, if any, apoptosis (9, 23, 56). The DNA breaks persist as long as the level of NaCl remains high, but, when NaCl is lowered, DNA repair activates immediately, and the DNA breaks are repaired (19, 23). This pattern is not restricted to tissue culture. Amazingly, numerous DNA breaks are present in vivo in cells of the normal mouse renal inner medulla (23), which can be attributed to the high level of NaCl that is normally present in renal medullary interstitial fluid (3). Despite the presence of DNA breaks in the inner medulla, apoptosis is rare there (63, 74). As in cell culture, DNA breaks persist in the renal medulla as long as the NaCl concentration remains high. However, the breaks are rapidly repaired when inner medullary osmolality is decreased by the diuretic furosemide (23).  k- g  D/ l8 O- h+ A
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These discoveries raise numerous questions. They make us wonder how cells exposed to high NaCl can cope with the continuous presence of DNA breaks. How can the cells transcribe broken DNA efficiently, and how can they replicate it safely Why do the cells apparently ignore the breaks Why don't they remain in cell cycle arrest, repair the DNA, or else undergo apoptosis, as with other stresses Is continued presence of the breaks necessary for adaptation to high NaCl Is there an alternative DNA damage response, modified by NaCl at the molecular level, so that the cells can survive and function despite the DNA breaks We do not yet have the answers to those questions, but we are beginning to have some understanding. In what follows, we present our current view of how high NaCl induces DNA breaks, how it inhibits the DNA damage response, and how the cells manage to cope (see also other recent reviews in Refs. 21 and 22).: h: _1 j7 w5 D9 C6 y7 {6 g

HYPERTONICITY INHIBITS THE USUAL DNA DAMAGE RESPONSE

High NaCl modifies the DNA damage response at the molecular level in several ways. Mre11 exonuclease is a nuclear protein that normally binds rapidly to DNA breaks, initiating the process of repair (14). However, high NaCl causes Mre11 to move from the nucleus to the cytoplasm, where it is unavailable to initiate DNA repair (19), and Mre11 stays in the cytoplasm even after the cells adapt to high NaCl (23). Chk1 becomes phosphorylated immediately after induction of DNA breaks by other genotoxic agents, initiating cell cycle arrest (5, 32). However, Chk1 is not phosphorylated in response to the DNA breaks that are induced by high NaCl (19, 23). Histone H2AX becomes phosphorylated at DNA double-strand breaks induced by ionizing radiation (55), which is a prerequisite for successful DNA repair (10, 54). The DNA breaks caused in cell culture by high NaCl, however, do not induce phosphorylation of histone H2AX (23). Furthermore, despite the existence of DNA breaks, H2AX is not phosphorylated in mouse renal inner medullas in vivo. We propose that inhibition by high NaCl of repair of normally occurring DNA breaks may cause them to accumulate, explaining how DNA becomes damaged in the presence of high NaCl.
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Remarkably, all the aspects of the DNA damage response that are lacking in cells as long as they are exposed to high NaCl become activated immediately when NaCl is reduced. Mre11 moves into the nucleus, histone H2AX and Chk1 become phosphorylated, and the DNA breaks disappear within a few hours (19, 23). Thus at least some components of the classic DNA damage response are inhibited by high NaCl. However, others are not. DNA damage-response proteins that are upregulated by high NaCl include GADD45 (11, 41, 43), p53 (17), and ataxia telangiectasia (AT)-mutated kinase (ATM) (33).( X$ L# D1 T$ y, C. E; t5 Q
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We speculate that high NaCl activates a nonclassic DNA damage response in which the DNA breaks are not religated but are modified to maintain DNA function without inducing chronic cell cycle arrest or apoptosis. That would involve an alternative protein complex that stabilizes the DNA breaks and maintains chromatin structure in cells exposed to high NaCl. Our preliminary results suggest that the Ku86/Ku70 heterodimer might be an essential part of such a complex (16). Cells deficient in Ku86 are hypersensitive to high NaCl, as manifested by profound inhibition of proliferation, aberrant mitosis, and increased chromatin fragmentation (16). Ku is a heterodimeric DNA end-binding complex composed of two proteins, Ku70 and Ku86. It is a major component of the complex involved in nonhomologous end joining of DNA double-strand breaks. It binds with high affinity to DNA ends, independent of their sequence or structure (45, 53, 62). Biochemical studies and the structure of the Ku heterodimer suggest that it acts as an alignment factor (67). We suppose that it helps stabilize the DNA breaks in cells adapted to high NaCl in a way that maintains DNA function, but that additional, unidentified proteins are involved. Further studies are needed to detail the molecular mechanisms involved in response to DNA breaks induced by high NaCl and to understand how cells cope despite their continued presence.9 K4 E. g4 r- a) j6 J6 d" O

OSMOTIC REGULATION

Not only are DNA breaks continuously present in renal medullary cells as long as they are exposed to high NaCl, but it now appears that the breaks may be sensors of hypertonicity that contribute to the protective osmoregulatory response. Other known effects of hypertonicity were previously proposed to be the sensors, including alterations in cell volume, in intracellular ionic strength, and in molecular crowding (28). Hypertonicity shrinks cells by osmosis, elevating the concentration of all intracellular components. Intracellular ionic strength rises, and intracellular macromolecules become more crowded, altering the activity of proteins, DNA, and other cellular macromolecules. Thus reduction of cell volume by hypertonicity alters the activity of numerous cellular constituents. Cells generally respond to hypertonicity by two successive processes, regulatory volume increase (RVI) (31) and accumulation of compatible organic osmolytes (73). The rapid initiation of RVI normalizes cell volume by accumulation of inorganic ions, followed by an osmotic influx of water. However, that still leaves high intracellular ionic strength. Accumulation of compatible organic osmolytes lowers intracellular ionic strength while maintaining cell volume. The benefit to the cells is that compatible organic osmolytes do not perturb macromolecular function like inorganic ions do. The kidneys maintain osmolality of the extracellular fluid constant at 290 mosmol/kgH2O by regulating the concentration and volume of the urine. Therefore, most cells do not normally experience hypertonicity. However, operation of the urinary concentrating mechanism entails a high concentration of NaCl in renal medullary interstitial fluid. The lowest normal concentration of inorganic salts (mainly NaCl) in renal medullary interstitial fluid is 600 mosmol/kgH2O, which occurs during prolonged water diuresis (2). The concentration of NaCl increases during prolonged antidiuresis, accompanied by accumulation of molar concentrations of urea, making the renal medulla a site of extreme osmotic stress. A vital part of the protective response is accumulation of compatible organic osmolytes. The predominant renal medullary organic osmolytes are sorbitol, glycine betaine (betaine), myo-inositol (inositol), and glycerophosphocholine (GPC) (7). Renal cells exposed to high salt in tissue culture accumulate the same compatible organic osmolytes (48). If accumulation of the compatible organic osmolytes is prevented, growth and survival of renal medullary cells exposed to high salt are impaired in tissue culture (72) and survival is impaired in vivo (35). Although accumulation of compatible organic osmolytes evidently protects cells from important harmful effects of hypertonicity, the protection is not complete. The DNA damage response is still inhibited, and DNA damage still remains.2 b  S5 ?& x2 Q7 s' z3 i( e5 E

In addition to organic osmolytes, renal inner medullary epithelial cells accumulate heat shock proteins when exposed to high salt both in vivo and in cell culture (8, 12, 50, 58). The heat shock protein response to hypertonicity is rapid, which provides protection while organic osmolytes are being accumulated (12). Furthermore, hsp70 is directly antiapoptotic. It inhibits apoptosis through several mechanisms, including prevention of formation of the apoptosome (4, 70). Targeted disruption of hsp70.1 sensitizes cells to osmotic stress in vitro and in vivo. Also, hsp70.1-deficient mouse embryonic fibroblasts tolerate less osmotic stress than do wild-type fibroblasts, and hsp70.1-deficient mice have increased apoptosis in their renal medullas (61).7 ?2 Z7 c# _7 ^. I% \- w
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Hypertonicity increases transcription of HSP70 and also of the genes responsible for accumulation of organic osmolytes, namely, aldose reductase (AR), which catalyzes the conversion of glucose to sorbitol, the betaine--aminobutyric acid transporter (BGT1), and the sodium-myo-inositol cotransporter (SMIT), which transport betaine and inositol, respectively, into the cells (7) (Fig. 3). The increased transcription is mediated by an enhancer, osmotic response element/tonicity-responsive enhancer (ORE/TonE), present in their 5'-flanking regions (7, 69). The urea transporter gene, UTA, is similarly regulated by hypertonicity (49) (Fig. 3) and is essential for optimal operation of the urinary concentrating mechanism (25). Hypertonicity-induced increases in transcription of these genes results from activation of the transcription factor TonE/ORE binding protein (TonEBP/OREBP) (37, 47, 69).
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REGULATION OF TonEBP/OREBP BY PROTEIN KINASES7 Y4 j4 g! R, ]

Like many other transcription factors, TonEBP/OREBP is controlled at multiple levels. Hypertonicity affects its distribution between nucleus and cytoplasm, its phosphorylation, its protein abundance, and its transactivation. Thus, at osmolalities near 300 mosmol/kgH2O, TonEBP/OREBP is present in both the nucleus and the cytoplasm. Hypertonicity shifts it to the nucleus, where it is available to regulate transcription, and hypotonicity shifts it to the cytoplasm (68). High NaCl transactivates TonEBP/OREBP, resulting in increased transcriptional activity (27). Hypertonicity also rapidly increases phosphorylation of TonEBP/OREBP on tyrosines and serines (13). The increase in phosphorylation within amino acids 548–1531 coincides with enhanced transactivation (27). Finally, after several hours, hypertonicity increases the abundance of TonEBP/OREBP mRNA and protein (37, 47).' Q* z! S4 P; g

Several different protein kinases are known to be involved in tonicity-induced activation of TonEBP/OREBP (Fig. 3) (59). Their combined activity is necessary for full tonicity-induced activation, but no one of them, alone, is sufficient. Furthermore, while we know that each of these kinases is activated by high NaCl, we understand less about how the tonicity is sensed and about possible interrelations between the kinases. The specific protein kinases known to be activated by hypertonicity include p38, Fyn, PKA, and ATM.9 B: }3 o& R. k9 ^$ @) Y
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Hypertonicity increases phosphorylation of p38, accompanied by an increase in its kinase activity (29, 34, 44). Inhibition of p38 reduces tonicity-dependent activation of TonEBP/OREBP (36, 57). Cytoskeletal effects of hypertonicity, mediated by Rac, are one sensor for hypertonic activation of p38 (Fig. 3) (65). It seems likely that this OSM pathway is involved in p38-mediated activation of TonEBP/OREBP, although there is not yet direct evidence that interrupting the pathway reduces hypertonic activation of TonEBP/OREBP.

Fyn is a nonreceptor tyrosine kinase that is activated by hypertonicity. Inhibition of Fyn by the pyrazolopyrimidine derivative PP2 or transfection of dominant-negative Fyn partially blocks hypertonic activation of an ORE/TonE reporter (36). Furthermore, hypertonic activation of an ORE/TonE reporter is attenuated in Fyn-deficient cells. Thus Fyn contributes to hypertonicity-induced activation of TonEBP/OREBP (Fig. 3).9 \1 a5 \. {4 E- Z3 n
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High NaCl also activates PKA, which contributes to activation of TonEBP/OREBP (26). H-89, an inhibitor of PKA, reduces tonicity-dependent increases in ORE/TonE reporter activity, induction of AR and BGT1 mRNAs, and TonEBP/OREBP transactivation. Overexpression of the catalytic subunit of PKA (PKAc) increases the activity of an ORE/TonE reporter and transactivates TonEBP/OREBP, while dominant-negative PKAc reduces activity of an ORE/TonE reporter. Finally, TonEBP/OREBP and PKAc coimmunoprecipitate, demonstrating physical association (26).

REGULATION OF TonEBP/OREBP BY ATM, A DNA DAMAGE-RESPONSE PROTEIN

There is no reason to believe that the protein kinases already mentioned are linked to DNA damage, but such a link is provided by ATM kinase, which is a DNA damage-response protein, whose gene is mutated in the human genetic disorder AT. In unstressed cells, ATM is a homodimer or higher-order multimer in which each partner blocks and inactivates the kinase domain of the other (1). Within moments after DNA double-strand breaks (DSBs), ATM undergoes intermolecular autophosphorylation at S1981, releasing fully active monomers (1). Nuclear ATM is recruited to sites of DSBs soon after DNA damage occurs. However, the initial signal for ATM activation may be the accompanying alteration of chromatin rather than the DSBs themselves (1, 60). Even a very few DSBs result in autophosphorylation of ATM throughout the nucleus, not just at DSBs, and perturbation of chromatin structure activates ATM even in the absence of DNA damage (reviewed in Ref. 60). When ATM is activated by DSBs, it phosphorylates and activates numerous targets, such as p53, MDM2, Chk2, BRCA1, and NBS1, that mediate cell cycle arrest, DNA repair, and apoptosis (60). As discussed above, high NaCl not only causes DSBs but inhibits their repair. Some DNA damage-response proteins, like Mre11, are inhibited by high NaCl, whereas others, like Ku86, are not. Recently, we found that elevating NaCl activates ATM and that ATM contributes to the tonicity-dependent activation of TonEBP/OREBP (33). Activation of ATM by high NaCl could be due to the DNA damage itself or to perturbation of chromatin structure, both of which could result from high NaCl (38, 40). TonEBP/OREBP contains amino acid sequences around S1197, S1247, and S1367 that match the consensus for ATM phosphorylation sites. These serines are contained in a region of TonEBP/OREBP (amino acids 548–1531), whose phosphorylation is increased by high NaCl (26). Wortmannin, which inhibits phosphatidylinositol kinase-related kinases including ATM, decreases tonicity-dependent activation of TonEBP/OREBP. Involvement of DNA-activated protein kinases in the response to hypertonicity had previously been suspected based on effects of LY-294002, an inhibitor similar to wortmannin (40). Wortmannin reduces activity of an ORE/TonE luciferase reporter and abundance of BGT1 mRNA (33). Studies of AT cells, which lack functional ATM, demonstrated that ATM is specifically involved. High NaCl-dependent TonEBP/OREBP transcriptional activity and transactivation are reduced in these cells, and these activities are restored when the AT cells are reconstituted with wild-type ATM, but not with ATM rendered inactive by an S1981A mutation (33). As mentioned above, TonEBP/OREBP has several serines that are putative ATM phosphorylation sites. Overexpression of wild-type TonEBP/OREBP in HEK293 cells stimulates ORE-dependent transcription much more than does overexpression of TonEBP/OREBP mutated at the putative ATM phosphorylation sites, indicating that these sites are important for TonEBP/OREBP activity (33). Finally, ATM physically associates with TonEBP/OREBP. ATM coimmunoprecipitates with TonEBP/OREBP and vice versa. Also, an antibody against ATM supershifts TonEBP/OREBP in electrophoretic mobility shift assays, indicating that the physical association is retained in the transcription complex.

PERSPECTIVE

We propose that the DNA DSBs (or the associated perturbation of chromatin) that are caused by hypertonicity activate ATM and that this contributes to hypertonicity-induced activation of TonEBP/OREBP (Fig. 3). It has been questionable whether there is a single sensor of hypertonicity that signals through a network of interrelated kinases or whether hypertonicity perturbs numerous cellular functions, leading to a unique combination of signals that together fully activate TonEBP/OREBP. We favor the latter. ATM is one of several kinases that contribute to activation of TonEBP/OREBP. Each is necessary for full activation, but none, alone, is sufficient. Strikingly, simply activating ATM by damaging DNA, does not of itself activate TonEBP/OREBP. Ionizing and ultraviolet radiation both damage DNA and activate ATM, but they do not activate TonEBP/OREBP (33). Additional signals are necessary. One signal is transmitted through the p38 pathway, likely triggered by cytoskeletal reorganization. Another trigger may be the oxidative stress that accompanies hypertonicity (75, 76), but the downstream components of this pathway are not yet known.: J: j, r; c% g4 p
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Sensing hypertonicity in mammalian cells has been variously attributed to changes in intracellular ionic strength (51, 64), cell volume (51), and molecular crowding (28). Now, additional perturbations have to be considered, including DNA damage, cytoskeletal alterations, and oxidative stress. Considering that most other functions of mammalian cells are much more complicated than those of yeast, the additional complexity of multiple sensors of hypertonicity and multiple pathways signaling osmotic regulation is not surprising.

FOOTNOTES
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