Department of Internal Medicine, University of Arkansas for Medical Sciences, and Department of Veterans Affairs Medical Center, Little Rock, Arkansas 72205
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ABSTRACT |
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Recovery from injury is usually
accompanied by cell replication, in which new cells replace those
irreparably damaged. After acute renal failure, normally quiescent
kidney cells enter the cell cycle, which in tubule segments is
accompanied by the induction of cell cycle inhibitors. We found that
after acute renal failure induced by either cisplatin injection or
renal ischemia, induction of the p21 cyclin-dependent kinase
(cdk) inhibitor is protective. Mice lacking this gene developed more
widespread kidney cell death, more severe renal failure, and had
reduced survival, compared with mice with a functional p21
gene. Here, we show induction of 14-3-3, a regulator of
G2-to-M transition, after acute renal failure. Our
findings, using both in vivo and in vitro models of acute renal
failure, show that this protein likely helps to coordinate cell cycle
activity to maximize recovery of renal epithelial cells from injury and
reduce the extent of the injury itself. Because in terminally
differentiated cells, these proteins are highly expressed only after
injury, we propose that cell cycle coordination by induction of these
proteins could be a general model of tissue recovery from stress and injury.
kidney failure; acute; p21 cyclin kinase inhibitor; cisplatin; ischemia
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INTRODUCTION |
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AFTER INJURY, MANY TYPES OF quiescent, terminally differentiated cells enter the cell cycle (38). In the kidney after acute renal failure, these cell types primarily include epithelial cells of proximal and distal tubules and collecting ducts (22, 34). This progression is controlled in part by the upregulation of genes coding for cyclin-dependent kinase (cdk) inhibitors, such as p21 (25), that check the cell cycle, primarily at the G1-to-S and G2-to-M transitions. We found that p21 induction is protective because mice lacking this gene, after either cisplatin injection or renal ischemia, developed more widespread kidney cell death, more severe renal failure, and had reduced survival, compared with mice with a functional p21 gene (21, 24).
Recently, it was shown that 14-3-3, another cell cycle inhibitor,
may also determine cell fate after injury (4, 5, 15).
After DNA damage, both p21 and 14-3-3
were induced in cells in
vitro, which led to cell cycle arrest. Without either inhibitor, injury
caused an uncoordinated cell cycle, resulting in increased cell death
(15). We now show 14-3-3
mRNA induction after both
cisplatin- and ischemia-induced acute renal failure in vivo.
This mRNA is expressed in kidney tubules previously described as
inducing p21 mRNA (25). After acute renal failure, the
increased mortality of this syndrome in mice lacking the p21
gene was most likely caused by the inability of the cells to induce
both p21 and 14-3-3
cell cycle inhibitors, which resulted in an
uncoordinated cell cycle. The uncoordinated cell cycle in kidney of
p21(
/
) mice was characterized by increased cell cycle
activity, increased nuclear size and cellular DNA content, and
ultimately more widespread cell death (Refs. 21 and
24 and this study).
To explore the roles of p21 and 14-3-3 in relevant in vitro models
of renal cell injury, we determined the effects of cisplatin and
hydrogen peroxide exposure on cells in which one or both genes were
deleted. Our results show that compared with wild-type cells, cells
with the gene deletions had much decreased survival after cisplatin or
peroxide exposure.
These studies are compatible with the idea that cell stress induces
pathways that compete between cell death and cell cycle arrest. In
wild-type cells, stress results in induction of cell cycle inhibitors
that lead to arrest, whereas in p21- and/or
14-3-3-deleted cells, similar stress causes cell death
pathways to predominate. Our results show that coordinated cell cycle
control, initially manifested as cell cycle inhibition, is necessary
for optimum recovery from acute renal failure and is a likely paradigm
for other types of epithelial cell injuries.
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METHODS |
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Mice and induction of acute renal failure. Mice carrying a deletion of a large portion of the p21 gene in which neither p21 mRNA nor p21 protein is expressed were obtained from Dr. Philip Leder (Harvard Medical School). Mice that were homozygous for the p21 deletion were selected from the offspring of heterozygous matings using Southern blotting of tail DNA as described (6). Wild-type homozygous littermates were selected as controls. Male mice from 8 to 15 wk of age were studied as described. The animals used in these studies were housed at the Veterinary Medical Unit at the John L. McClellan Memorial Veterans' Hospital, Little Rock, AR. Survival surgery protocols were approved by the Animal Care and Use Committee, Department of Veterans Affairs. When appropriate, animals were painlessly killed according to methods of euthanasia approved by the Panel on Euthanasia of the American Veterinary Medical Association.
Ischemia was induced in anesthetized (pentobarbital sodium, 50 mg/kg ip) male mice by exposure of the kidneys through a midline incision under sterile conditions. The kidneys were decapsulated, and both renal hila were clamped with small arterial clamps for 50 min and released. During the operation, the mice received ~1 ml of saline intraperitoneally. Sham operations were also performed, in which the kidneys were manipulated as described without induction of ischemia. After surgery, the animals were returned to their cages and allowed free access to food and water. Cisplatin was administered by a single intraperitoneal injection to mice at 20 mg/kg.Morphological assessment. At various times after ischemia or cisplatin treatment, kidneys were removed, immersed in 4% neutral-buffered formaldehyde, and fixed for 48-72 h. Tissues were embedded in paraffin, and sections were cut with a microtome and placed on slides. The tissues were used as described below or were stained with hematoxylin-eosin or periodic acid-Schiff.
mRNA isolation and Northern blotting.
Poly[A]+ RNA was isolated from kidney using a RiboSep kit
(Becton-Dickinson), electrophoresed, and blotted as described
(25, 33). Briefly, tissue was lysed in the presence of SDS
and proteinase K. After digestion of the lysate for 2 h at 45°C,
it was applied to an oligo(dT) column. After being washed with a buffer
containing 0.5 M NaCl, poly[A]+ RNA was eluted with 10 mM
Tris, pH 7.5, 1 mM EDTA, and 0.05% sarkosyl. The
polyadenylated RNA (5 µg) was denatured by heating in a
buffer containing formamide and formaldehyde and electrophoresed through 1% agarose in denaturing buffer. After electrophoresis, the
gel was washed with 20× SSC (1× SSC = 0.15 M NaCl, 0.015 M sodium citrate), and the RNA was transferred to nitrocellulose membranes by upward diffusion. After prehybridization, the RNA was
hybridized with a 32P-radiolabeled probe (14-3-3 cDNA;
courtesy of Dr. Bert Vogelstein). After hybridization, the filters were
washed, air-dried, and autoradiographed. Hybridization to a probe
specific for GAPDH mRNA was used as an internal control. We have
previously shown that the levels of this mRNA do not vary appreciably
after acute renal failure (22, 33) when measured either by
Northern hybridization or RT-PCR.
In situ localization of 14-3-3 mRNA.
In situ hybridization of 14-3-3
mRNA on kidney sections was
performed as previously described (22, 25), using
paraffin-embedded tissue. The specificity of the hybridization was
controlled by hybridization with "sense" probes, which did not
result in any color reaction on the sections. Probes for in situ
hybridization were labeled with digoxigenin using in vitro
transcription of a linearized murine 14-3-3
plasmid in which the
14-3-3
cDNA had been inserted in pBluescript KS(+) between T7 and T3 promoters.
Nuclei preparation and in situ hybridization for DNA quantification. Kidneys were homogenized with a Potter-Elvehjem grinder in buffer (10 ml for 2 kidneys) containing 10 mM HEPES, pH 7.6, 25 mM KCl, 1 mM EDTA, 10% glycerol, and 1.8 M sucrose. The homogenate was layered on 2.2 ml of the above buffer and centrifuged with an SW60 rotor for 30 min at 24,000 rpm and 2°C. The nuclear pellets were combined in 0.1 ml PBS for 2 kidneys. Fixative (3:1 methanol-acetic acid) was added, and the nuclei were pelleted at 500 rpm for 10 min. The nuclei were resuspended in fixative and applied to silanized glass slides. The dried nuclei were treated with thiocyanate for 10 min at 80°C, digested with 75 µg/ml pepsin for 15 min at 37°C, and postfixed in formaldehyde. The slides were hybridized with a biotinylated P1 mouse ES probe (locus D15 MIT 13; Genome Systems) for 16 h at 37°C in buffer containing 60% formamide, 2× SSC, 10% dextran sulfate, and 0.25 µg/ml denatured salmon DNA. Slides were washed and incubated with avidin-conjugated peroxidase in 4× SSC and 5% nonfat dry milk. The reaction was developed with 3,3'-diaminobenzidine as a substrate and washed with water, and the nuclei were stained with hematoxylin. The slides were dehydrated through ethanol, transferred into xylene, and mounted under coverslips.
Tissue culture cells and treatments.
HCT116 cells containing either wild-type p21 and
14-3-3 genes, or with p21(
/
), and
14-3-3
(
/
) deletions (5) were obtained from Dr. B. Vogelstein. The cells were cultured in McCoy's medium containing 10% fetal bovine serum. Cells were treated at ~75% confluence with 0-50 µM cisplatin or 0-400 µM hydrogen
peroxide for 24 h. Cell survival after treatments was determined
by trypan blue exclusion. Statistical analyses of survival curves were
evaluated using the F-probability distribution with GraphPad
Prism 3.02.
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RESULTS |
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Induction of 14-3-3 mRNA.
Induction of 14-3-3
after acute renal failure was determined by
using mRNA isolated from mice (Fig. 1).
There was no 14-3-3
mRNA present in untreated kidney (lanes
1 and 2), but it was induced to high levels by both
renal ischemia (lanes 3 and 4) and
cisplatin injection (lanes 5 and 6). Also, the
persistence of its induction is seen by its presence 3 days after
cisplatin injection (lane 6).
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In situ hybridization for localization of 14-3-3 mRNA.
In situ hybridization before (Fig. 2, A and
C) and 24 h after
cisplatin injection (Fig. 2, B and D) in both
wild-type (Fig. 2, A and B) and
p21(
/
) (Fig. 2, C and D) mouse
kidney sections showed induction of 14-3-3
mRNA in tubules of the
distal nephron. A similar distribution was found in sections after
ischemia (data not shown). There were no quantitative
differences in 14-3-3
mRNA induction when wild-type and
p21(
/
) mouse kidney are compared using Northern blot
analysis (data not shown).
|
Polyploidy determination by nuclear morphology and in situ
hybridization.
Many nuclei in kidney sections from p21(/
) mouse kidney
after acute renal failure were larger than nuclei in similar sections from p21(+/+) mice or from mice without renal failure (Fig.
3). To confirm that this represented
polyploidy of the DNA, we performed in situ hybridization (Fig.
4) using a probe specific for mouse chromosome 15 on isolated interphase nuclei from kidney of untreated and cisplatin-injected mice, both p21(+/+) and
p21(
/
). Nuclei isolated from untreated mouse kidney
(Fig. 4A) showed two areas of hybridization, indicative of
diploid chromosome number. Similar results were obtained using nuclei
isolated from kidney of untreated p21(+/+) and
p21(
/
) mice and from cisplatin-injected
p21(+/+) mice. Nuclei isolated from kidney of
cisplatin-treated p21(
/
) mice (Fig. 4B)
frequently showed many areas of hybridization, indicative of polyploidy
of the genome.
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|
Tissue culture model of cisplatin- or oxidant injury-induced acute
renal failure.
Cells were grown to ~75% confluence and exposed to either cisplatin
(10-50 µM) or hydrogen peroxide (50-400 µM). The numbers of surviving cells, as measured by trypan blue exclusion, were compared
with numbers of surviving cells in control cultures (0 µM cisplatin
or peroxide) after 24-h exposure (Fig.
5). Comparison of the survival curves by
F-probability distribution showed that survival of
p21(/
) cells or 14-3-3
(
/
) cells was
significantly lower than wild-type cells (P = 2.0 × 10
8, cisplatin, p21 deletion;
P = 0.0070, peroxide, p21 deletion; P = 0.00010, cisplatin, 14-3-3
deletion;
P = 0.047, peroxide, 14-3-3
deletion). However, the effect of either deletion was not significantly
different from each other (P = 0.154, cisplatin; P = 0.124, peroxide).
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DISCUSSION |
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Cell cycle regulation.
The control of the cell cycle involves a complex interaction of both
positive and negative factors controlling mRNA transcription and
translation, protein activity and stability, and compartmentalization of enzymes and substrates. This cell cycle control primarily occurs at
the G1-to-S and G2-to-M transitions. In a
DNA-damage model, it is dependent on the induction of two genes,
p21 and 14-3-3 (9, 15). In the
replication of cells in vitro, expression of one of these genes in the
absence of the other had different effects on cell survival. Whereas
p21 expression caused cell cycle inhibition, expression of
14-3-3
in the absence of p21 expression caused
uncoordinated replication, an increase in DNA content, and eventual
cell death (15). In DNA-damaged cells, the absence of
either gene resulted in increased cell death.
Cell cycle control in acute renal failure.
Acute renal failure caused by disparate injuries, i.e.,
ischemia or nephrotoxic drugs (e.g., cisplatin), results in
severe and acute reduction in the glomerular filtration rate and in
clearance of serum nitrogenous wastes, such as creatinine and blood
urea nitrogen (BUN). There are also varying degrees of kidney cell death, especially involving the S3 segment of the proximal tubules in
the deep cortex. We have previously shown a rapid and high level
induction of a cell cycle inhibitory protein, p21, in murine kidney
after acute renal failure (25). This induction was
beneficial because after both cisplatin and ischemic acute
renal failure (21, 24) there was increased and more
widespread cell death in kidney of p21(/
) mice compared
with p21(+/+) mice. Along with the more severe cytotoxicity,
we found increased cell cycle activity in kidney of
p21(
/
) mice and speculated that this increased cell
cycle activity could have detrimental effects.
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ACKNOWLEDGEMENTS |
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We thank Dr. Philip Leder (Harvard Medical School) for providing
several heterozygous mice carrying the p21 gene deletion and
for providing a probe for screening. We thank Dr. Bert Vogelstein (Johns Hopkins University School of Medicine) for providing the probe
for 14-3-3 mRNA and HCT116 cells and derivatives with p21 and 14-3-3
gene deletions.
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FOOTNOTES |
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This work was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK-54471 and with resources of and the use of facilities at the John L. McClennan Memorial Veterans Hospital, Little Rock, AR.
Address for reprint requests and other correspondence: P. M. Price, Univ. of Arkansas for Medical Sciences, 4300 West 7th St., Mail Route 151, Little Rock, AR 72205 (E-mail: PricePeterM{at}uams.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
May 29, 2002;10.1152/ajprenal.00078.2002
Received 25 February 2002; accepted in final form 14 May 2002.
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