Published online before print July 28, 2005, doi: 10.1161/01.RES.0000179226.34112.6d
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© 2005 American Heart Association, Inc.
Integrative Physiology |
Cardiomyocyte-Specific Knockout and Agonist of Peroxisome Proliferator–Activated Receptor-
Both Induce Cardiac Hypertrophy in Mice
From the Department of Pharmacology (S.Z.D., R.M.M.), Department of Molecular and Integrative Physiology (S.Z.D., C.Y.I., R.M.M.), Department of Pediatrics and Communicable Diseases (M.W.R.), and the Metabolism Endocrinology and Diabetes Division (R.M.M.), Department of Internal Medicine, University of Michigan Medical School, Ann Arbor; and the Vascular Research Division (D.S.M.), Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Richard M. Mortensen, Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109. E-mail rmort{at}umich.edu; or Dr David S. Milstone, E-mail milstone@rascal.med.harvard.edu
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Abstract |
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Peroxisome proliferator–activated receptor (PPAR)-
is required for adipogenesis but is also found in the cardiovascular system, where it has been proposed to oppose inflammatory pathways and act as a growth suppressor. PPAR- agonists, thiazolidinediones (TZDs), inhibit cardiomyocyte growth in vitro and in pressure overload models. Paradoxically, TZDs also induce cardiac hypertrophy in animal models. To directly determine the role of cardiomyocyte PPAR-, we have developed a cardiomyocyte-specific PPAR-–knockout (CM-PGKO) mouse model. CM-PGKO mice developed cardiac hypertrophy with preserved systolic cardiac function. Treatment with a TZD, rosiglitazone, induced cardiac hypertrophy in both littermate control mice and CM-PGKO mice and activated distinctly different hypertrophic pathways from CM-PGKO. CM-PGKO mice were found to have increased expression of cardiac embryonic genes (atrial natriuretic peptide and ß-myosin heavy chain) and elevated nuclear factor 
B activity in the heart, effects not found by rosiglitazone treatment. Rosiglitazone increased cardiac phosphorylation of p38 mitogen-activated protein kinase independent of PPAR-, whereas rosiglitazone induced phosphorylation of extracellular signal–related kinase 1/2 in the heart dependent of PPAR-. Phosphorylation of c-Jun N-terminal kinases was not affected by rosiglitazone or CM-PGKO. Surprisingly, despite hypertrophy, Akt phosphorylation was suppressed in CM-PGKO mouse heart. These data show that cardiomyocyte PPAR- suppresses cardiac growth and embryonic gene expression and inhibits nuclear factor B activity in vivo. Further, rosiglitazone causes cardiac hypertrophy at least partially independent of PPAR- in cardiomyocytes and through different mechanisms from CM-PGKO.
Key Words: peroxisome proliferator–activated receptor- • thiazolidinediones • cardiac hypertrophy • cardiomyocytes • knockout
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Introduction |
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Gene-inactivation studies have established the role of nuclear transcription factor PPAR-
in trophoblast function,1 adipocyte differentiation,1–3 mammary gland function,4 fertility,4 insulin resistance,5–7 liver function,8 and prostate cancer.9 The role of PPAR- in suppression of growth and inflammation in the cardiovascular system has been inferred by determining the effects of its agonists, thiazolidinediones (TZDs),10–13 although PPAR- does not always mediate the effects of TZDs.14–16
Although cardiac overexpression of PPAR-
or deletion of PPAR-
causes cardiac hypertrophy,17,18 the role of PPAR- in the heart has been controversial.19 PPAR- agonists inhibit mechanical stress-induced hypertrophy of cultured neonatal rat ventricular cardiomyocytes, reflecting, at least in part, inhibition of nuclear factor B (NF-B).11 Similarly, PPAR- agonists inhibit cardiac hypertrophy induced by aortic constriction in rats and mice.10,20 Cardiac hypertrophy induced by the pressure overload is also slightly more pronounced in heterozygous PPAR-–deficient mice compared with wild-type controls.10
However, TZDs increase the incidence of congestive heart failure in clinical trials,21 and the approved dosage is limited by the dose of TZD that induces cardiac hypertrophy in mice, rats, and dogs.22–25 At these limited doses, cardiac hypertrophy does not occur in humans.26,27 These actions by TZDs may occur because of expanding blood volume.21,22,25 However, an essential question is whether or not any of these effects are directly attributable to cardiac PPAR- activation.
In this study, we used cardiomyocyte-specific knockout to determine the physiological function of PPAR- in cardiomyocytes and the "on-target" and "off-target" effects of TZDs in cardiac hypertrophy.
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Materials and Methods |
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Materials
Rosiglitazone chow (0.005% rosiglitazone) was produced by mixing with 5001 rodent chow (Harlan Teklad). Daily food consumption was 0.2 g chow/g body weight per day, which delivers a rosiglitazone dose of 10 mg/kg body weight per day. Other reagents were purchased from Sigma-Aldrich (St Louis, Mo), except when indicated otherwise.
Animals
MHC-Cre mice (Cre driven by -myosin heavy–chain [MHC] promoter)28 were bred to floxed PPAR- mice29 to eventually obtain cardiomyocyte-specific PPAR-–knockout (CM-PGKO) mice (homozygous floxed PPAR- and MHC-Cre positive). CM-PGKO mice were bred to homozygous floxed PPAR- mice to generate both CM-PGKO mice and littermate control mice (homozygous floxed PPAR- and MHC-Cre negative). All animal protocols were approved by the University Committee on Use and Care of Animals of the University of Michigan.
Male (8 to 10 weeks of age, 5 mice per group) CM-PGKO mice and littermate control mice were treated with either regular chow or rosiglitazone (10 mg/kg per day) chow for 4 weeks. To observe cardiac size of CM-PGKO mice at older age, 1 additional group of 6-month-old male CM-PGKO mice and littermate control mice were included (5 mice for each group).
Southern Blot Analysis
Southern blot was performed as previously described.2 Briefly, genomic DNA was isolated from the heart of a littermate control mouse and from the heart and other tissues of a CM-PGKO mouse, digested with BamHI, separated by electrophoresis, and transferred to nylon membrane. The membrane was then hybridized with a 32P-labled DNA probe derived from PPAR- gene (3'-probe).2
Western Blot Analysis
Total protein was isolated from mouse hearts, subjected to electrophoresis, and transferred to polyvinylidene difluoride membranes as described previously.30 Membranes were incubated with primary antibodies (listed in online data supplement available at http://circres.ahajournals.org) and followed by incubation in secondary anti-sera conjugated with horseradish peroxidase. Detection and quantification were performed as described previously.30
Echocardiographic Studies
Transthoracic echocardiography was performed on 6-month-old male CM-PGKO mice and littermate control mice (5 mice in each group) as described previously.31 The following parameters were recorded or derived: left-ventricular fractional shortening (FS), ejection fraction (EF), stroke volume (SV), cardiac index, velocity of circumferential fiber shortening (Vcfc), heart rate (HR), isovolumic relaxation time (IVRT), E-wave/A-wave ratio (E/A), and mitral valve E-wave deceleration time (Dec T).
Cardiac Hypertrophy Estimation
Mice were weighed and anesthetized with Pentobarbital IP injection (70 mg/kg). Hearts were removed and ventricles were dissected for weighing. Tibiae were dissected and measured. Ventricular weight to body weight ratio (VW/BW) (milligrams per gram) and/or ventricular weight to tibia length ratio (VW/TL) (milligrams per millimeter) were used as indicators of cardiac size. Left ventricles were then snap-frozen in liquid nitrogen for further analyses.
Histological Analysis
Six-month-old CM-PGKO and littermate control mice were used for histology.10 Microtome sections were stained with hematoxylin/eosin (H&E) or trichrome. Cardioyocyte cross-sectional areas were measured using NIH ImageJ 1.31V (Bethesda, Md). Mean cardiomyocyte cross-sectional areas were calculated by averaging the measurements of 100 cells from sections.
Expression of Cardiac Genes
The following genes were assayed using reverse-transcription quantitative PCR (RT-QPCR)32: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), ß-MHC, sarcoplasmic reticulum calcium ATPase 2 (SERCA 2), and phospholamban (PLBN). SYBR green was used as a universal fluorescent probe and GAPDH was used as an endogenous control.
Determination of NF-B Activity by Electromobility Gel Shift Assay
Electromobility gel shift assay was performed as previously described.11 Briefly, nuclear extracts from left ventricles were incubated with 32P-labeled probe containing the consensus NF-B–binding site and then separated from unbound probe by electrophoresis. Autoradiography was performed using an imaging screen and the results were scanned using a molecular imager FX and quantified using QuantityOne software (Bio-Rad Laboratories).
Statistical Analysis
The results were presented as mean±SE and analyzed using Prism (GraphPad Software Inc). Statistical comparisons between groups were performed by Student t test or nonparametric (Mann–Whitney) test. Groups were considered significantly different if probability values were <0.05.
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Results |
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CM-PGKO Mouse Model
CM-PGKO mice were born in the expected Mendelian ratio and survived to adulthood. Southern blot analysis revealed an 8-kb restriction fragment (Figure 1A), indicating successful Cre-mediated recombination, in hearts only from CM-PGKO mice. Other tissues from these mice and hearts from littermate controls revealed only a 10-kb restriction fragment, indicating no recombination and persistence of the floxed PPAR-
allele (Figure 1A). The floxed PPAR- allele was also detected in CM-PGKO hearts (Figure 1A), probably reflecting contributions from other cell types including endothelial cells, smooth muscle cells, and fibroblasts.33 The ratio of floxed allele to recombined allele is consistent with near-complete recombination in cardiomyocytes.34,35 Western blotting revealed that 93.5±2.4% of PPAR- protein was eliminated in hearts from CM-PGKO mice compared with littermate controls (Figure 1B). This suggests that the majority of cardiac PPAR- protein is in myocytes that contribute the majority of the cardiac cellular volume. Residual PPAR- protein may be from unrecombined cardiomyocytes but also nontargeted endothelial cells, smooth muscle cells, and fibroblasts. These results are similar to other published studies of cardiomyocyte-specific gene inactivation.34,35
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PPAR- Deficiency in Cardiomyocytes Causes Cardiac Hypertrophy
To determine whether PPAR- alters growth in cardiomyocytes, we evaluated the VW/BW and/or VW/TL ratio as indications of cardiac size in CM-PGKO mice and littermate controls. Body weights and blood glucose levels of CM-PGKO mice were not significantly different from those of their littermate controls at 6 months of age (body weight, 34.5±2.1 g versus 35.5±3.3 g; blood glucose, 7.78±0.47 mmol/L versus 7.39±0.37 mmol/L, respectively; both P>0.05). Age-progressive cardiac hypertrophy was observed in CM-PGKO mice: <10% at age 3 months and 
22% at age 6 months, and the VW/BW of both ages were significantly greater than that of the littermate controls (Figure 2A and 2B). The VW/BW ratio increased with age in CM-PGKO mice but decreased with age in littermate controls between 3 and 6 months of age (Figure 2A and 2B). Cardiac hypertrophy in CM-PGKO mice was also revealed by histological analysis (H&E staining) at 6 months of age (Figure 2C). The size of cardiomyocytes was determined by measuring the mean cardiomyocyte cross-sectional areas. CM-PGKO mice have significantly larger cardiomyocytes than littermate control mice at 6 months of age (Figure 2D and 2E). Trichrome was used to stain for collagen deposition, and no significant difference was detected between CM-PGKO mice and littermate control mice (data not shown). Age-matched MHC-Cre mice have similar cardiac size as littermate control mice (VW/BW, 3.78±0.13 mg/g versus 3.88±0.12 mg/g at 3 months of age, respectively, with no significant difference in body weights).
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Preservation of Systolic Cardiac Function in the Absence of Cardiomyocyte PPAR-
Echocardiographic assessment was used to evaluate resting systolic cardiac function in 6-month-old CM-PGKO mice and their littermate controls. There were no significant differences between the 2 groups with respect to measures of systolic function (Table 1). Not surprisingly, although the differences did not reach statistical significance, there was a trend toward slight increases in the left-ventricular FS, EF, cardiac index, and Vcfc in 6-month-old CM-PGKO mice, suggesting that there may be a subtle improvement in systolic function as a result of increased numbers of contractile units. It supports that the cardiac hypertrophy noted in the CM-PGKO mice is likely to be a primary effect of increased contractile protein synthesis and not a compensatory process attributable to diminished cardiac systolic performance. Interestingly, there was a significantly lower resting HR in the CM-PGKO mice compared with their littermate controls (Table 1). Because measures of diastolic performance correlate with HR, there were trends toward reduced IVRT, increased E/A ratio, and decreased Dec T in the CM-PGKO mice compared with littermate controls (Table 1), although none of the differences in diastolic function was statistically significant.
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Rosiglitazone Causes Cardiac Hypertrophy in Mice at Least Partially Independent of Cardiomyocyte PPAR-
Rosiglitazone and other TZDs, including pioglitazone, have been shown to increase heart weight in mice, rats, and dogs.22–25 To evaluate the role of PPAR- in this process, 8- to 10-week-old male CM-PGKO mice and littermate controls were treated with 10 mg/kg per day rosiglitazone mixed in chow. After 4 weeks of treatment, cardiac size was evaluated by measuring VW/BW and VW/TL. As shown in Figure 3 (and online Table I), rosiglitazone caused significant cardiac hypertrophy in littermate controls and, to a lesser extent, CM-PGKO mice. No significant difference was detected in the cardiomyocyte cross-sectional areas after rosiglitazone treatment, possibly because of the sensitivity of this method.
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PPAR- Deficiency in Cardiomyocytes but Not Rosiglitazone Induces ANP and ß-MHC Expression
Pathological cardiac hypertrophy, particularly that induced by pressure overload, is associated with a cardiac gene expression program, including increased expression of ANP, BNP, ß-MHC, and decreased expression of SERCA 2 and PLBN.32 To establish whether this feature also accompanies cardiac hypertrophy induced by pharmacological activation and/or genetic inactivation of PPAR-, we used RT-QPCR to determine the effects of CM-PGKO and rosiglitazone on expression of these cardiac genes. Hearts from CM-PGKO mice showed increased expression of embryonic genes ANP and ß-MHC (Figure 4), suggesting that PPAR- normally suppresses their expression. However, expression of genes BNP, SERCA 2, or PLBN was not changed. In contrast, rosiglitazone did not alter expression of any of these genes in either CM-PGKO mice or littermate controls (Figure 4).
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PPAR- Deficiency in Cardiomyocytes but Not Rosiglitazone Elevates NF-B Activity
PPAR- agonist troglitazone was shown to inhibit NF-B activation of cultured cardiomyocytes stimulated by mechanical stress.11 However, the in vivo function of PPAR- on NF-B activation in the heart is unknown. Electromobility gel shift assay revealed significantly higher NF-B–binding activity in nuclear extracts from hearts of CM-PGKO mice (Figure 5), suggesting that PPAR- tonically limits NF-B activation. Because NF-B is sufficient to mediate hypertrophic growth of cardiomyocytes in vitro36 it is likely that NF-B activation leads to cardiac hypertrophy in CM-PGKO mice. Rosiglitazone was not found to change the NF-B binding activity in either CM-PGKO mouse hearts or littermate control mouse hearts. These results further support that genetic deficiency and pharmacological activation of PPAR- activates different hypertrophic pathways.
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Rosiglitazone but Not PPAR- Deficiency in Cardiomyocytes Activates MAPK Pathways
MAPKs are important mediators in cardiac hypertrophy.37,38 TZDs were shown to phosphorylate and activate mitogen-activated protein kinase (MAPK) pathways including p38-MAPK, extracellular signal–related kinase (ERK) 1/2, and c-Jun N-terminal kinases (JNKs) in other cell types.39–43 As shown in Figure 6, rosiglitazone induced phosphorylation of p38-MAPK and ERK1/2 in littermate control mouse hearts significantly, whereas the phosphorylation levels were not significantly different in CM-PGKO mouse hearts compared with littermate controls (Figure 6A through 6D). The effect of rosiglitazone on p38-MAPK persisted in CM-PGKO mouse hearts (Figure 6A and 6B), showing that activation of p38-MAPK is independent of cardiomyocyte PPAR-. However, the activation of ERK1/2 requires cardiomyocyte PPAR- because the effect of rosiglitazone on ERK1/2 was abolished by the PPAR- deficiency (Figure 6C and 6D). The increase in ERK1/2 phosphorylation may contribute to the hypertrophy in littermate control mice, which may account for the lower increase in cardiac size in CM-PGKO mice with rosiglitazone treatment. Neither rosiglitazone nor PPAR- deficiency affected total p38-MAPK or ERK1/2 protein level (Figure 6A through 6D). Neither phosphorylation nor total levels of JNK1 and JNK2 were changed by rosiglitazone or cardiomyocyte PPAR- deficiency (Figure 6E and 6F).
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Data in the online data supplement show that CM-PGKO did not significantly affect mRNA or protein levels of genes related to lipid or glucose metabolism (online Figures I and II) and that, surprisingly, Akt phosphorylation was decreased in CM-PGKO mouse hearts (online Figure III). Phosphorylation of mammalian target of rapamycin was not affected (online Figure III). AMP-activated protein kinase has a controversial role in cardiac hypertrophy and was found to be stimulated by rosiglitazone independent of PPAR- (online Figure IV). The TZD and CM-PGKO effects in cardiomyocytes are summarized in Table 2.
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Discussion |
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Cardiac hypertrophy is characterized by increased protein synthesis44 and size of existing cardiomyocytes,45 leading to increased cardiac muscle mass.46 Agonists of nuclear receptor PPAR-
have been shown to inhibit both protein synthesis and cardiac hypertrophy induced by pressure overload.10,11 To elucidate the physiological function of PPAR- in cardiomyocytes, we used Cre-loxP system to genetically inactivate this gene specifically in cardiomyocytes of CM-PGKO mice.
CM-PGKO mice displayed age-progressive cardiac hypertrophy, indicating that PPAR- normally suppresses cardiomyocyte growth. Despite this hypertrophy, the resting cardiac systolic function in CM-PGKO mice was comparable to littermate control mice at the age of 6 months. In fact, at this time point, there may be a subtle improvement in systolic function over baseline, which may lead to the lower resting HR that was noted. Whether function will be maintained as these mice continue to age will need to be further evaluated. What is evident is that the hypertrophy caused by cardiomyocyte PPAR- inactivation is not a secondary effect of diminished cardiac function but may be a primary effect of increased protein synthesis and new myofibril assembly.
Interestingly, cardiac expression levels of the embryonic genes ANP and ß-MHC were elevated in CM-PGKO mice, suggesting that PPAR- normally limits such expression in adult hearts. However, other genes typically altered in pressure overload–induced cardiac hypertrophy were not changed in CM-PGKO mice. Pressure overload clearly activates numerous signaling pathways, each of which is responsible for the activation or suppression of specific gene expression.38,47 It is, therefore, not surprising that selective inhibition of a single signaling pathway results in altered expression of only a subset of the cardiac genes. Similarly, ß-MHC was the only embryonic gene altered in cardiac hypertrophy associated with cardiomyocyte-restricted genetic deficiency of the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10).48
NF-B is necessary and sufficient for hypertrophic growth of cardiomyocytes in vitro.36 Elevated activity of NF-B in CM-PGKO mouse hearts implies that the interaction between these 2 nuclear transcription factors is important in regulating cardiac growth in vivo as well. In normal animals, PPAR- may inhibit NF-B activation and limit cardiomyocyte growth. Genetic deficiency of cardiomyocyte PPAR- could relieve this inhibition, resulting in increased NF-B activation and cardiac hypertrophy. Such effects may reflect direct interaction between PPAR- and the NF-B regulatory machinery, such as inhibitor B, inhibitor B kinase, etc, or indirect effects via altered transcription of other genes. It is also possible that PPAR- deficiency in cardiomyocytes may change the availability of cofactors (eg, PPAR- coactivator 1) or heterodimeric partners (retinoid X receptors) and contribute to the phenotype.
PPAR- agonist rosiglitazone also caused cardiac hypertrophy in mice. However, previous studies10,20 using pioglitazone have not reported hypertrophy. This apparent discrepancy may reflect different properties and/or doses of the TZDs studied. Rosiglitazone also induced cardiac hypertrophy in CM-PGKO mice although to a lesser extent, suggesting that this effect does not completely require PPAR- in cardiomyocytes. Rosiglitazone-induced hypertrophy may occur via PPAR-–independent effects in cardiomyocytes or PPAR- in nonmyocyte cells or may be secondary to blood volume expansion.21,25 Studies of embryonic stem cell and/or cancer cell growth have revealed that TZDs have other effects apparently independent of PPAR-.14–16
Three major subfamilies of MAPKs, p38-MAPKs, ERKs, and JNKs, are all involved in cardiac hypertrophy.38 Our results showed that rosiglitazone activated p38-MAPK independent of cardiomyocyte PPAR-. This might be part of the mechanism by which rosiglitazone induces cardiac hypertrophy. TZDs have been shown to activate p38-MAPK independent of PPAR- in other cell types.39 Rosiglitazone significantly increased the phosphorylation of ERK1/2 through a PPAR-–dependent mechanism. Because rosiglitazone caused cardiac hypertrophy in CM-PGKO mice as well, but less than in littermate control mice, the activation of ERK1/2 may contribute particularly to cardiac hypertrophy induced by rosiglitazone in littermate control mice. Rosiglitazone has been shown to increase adiponectin levels,49 which can activate ERKs in the heart.50 ERK activation is unlikely to be through adiponectin because it is dependent on cardiomyocyte PPAR-. Given that activation of either ERKs or p38-MAPK is sufficient to induce hypertrophy,51,52 it is not surprising that rosiglitazone causes hypertrophy without the activation of JNK1 and JNK2. Taken together, these results indicate that rosiglitazone and cardiomyocyte PPAR- deficiency cause cardiac hypertrophy through different and unrelated mechanisms.
These studies demonstrate that cardiomyocyte PPAR- inactivation in vivo causes cardiac hypertrophy, likely through NF-B activation. Rosiglitazone induces cardiac hypertrophy partially independent of cardiomyocyte PPAR-, possibly through activation of p38-MAPK, the activation of which is sufficient to induce hypertrophy.52 Activation of ERK1/2 may also contribute to hypertrophy in control animals. Overall, genetic deficiency of PPAR- in cardiomyocytes and rosiglitazone activate different hypertrophic pathways. These results provide more mechanistic insight about PPAR- actions in heart and may provide guidance for designing new PPAR- agonists with fewer cardiac side effects.
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Acknowledgments |
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This work was funded by a pilot project and cores of the Michigan Diabetes Research and Training Center (NIH5P60 DK20572 from the National Institute of Diabetes and Digestive and Kidney Diseases and R01HD040895 (D.S.M.) from the National Institute of Child Health and Human Development).
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Footnotes |
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Original received February 25, 2005; revision received July 11, 2005; accepted July 15, 2005.
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