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• W2010438778 abstract "Many of the studies of acute renal injury have been conducted in young mice usually during their rapid growth phase; yet, the impact of age or growth stage on the degree of injury is unknown. To address this issue, we studied three forms of injury (endotoxemic-, glycerol-, and maleate-induced) in mice ranging in age from adolescence (3 weeks) to maturity (16 weeks). The severity of injury within each model significantly correlated with weight and age. We also noticed a progressive age-dependent reduction in renal cholesterol content, a potential injury modifier. As the animals grew and aged they also exhibited stepwise decrements in the mRNAs of HMG CoA reductase and the low density lipoprotein receptor, two key cholesterol homeostatic genes. This was paralleled by decreased amounts of RNA polymerase II and the transcription factor SREBP1/2 at the reductase and lipoprotein receptor gene loci as measured by chromatin immunoprecipitation. Our study shows that the early phase of mouse growth can profoundly alter renal susceptibility to diverse forms of experimental acute renal injury. Many of the studies of acute renal injury have been conducted in young mice usually during their rapid growth phase; yet, the impact of age or growth stage on the degree of injury is unknown. To address this issue, we studied three forms of injury (endotoxemic-, glycerol-, and maleate-induced) in mice ranging in age from adolescence (3 weeks) to maturity (16 weeks). The severity of injury within each model significantly correlated with weight and age. We also noticed a progressive age-dependent reduction in renal cholesterol content, a potential injury modifier. As the animals grew and aged they also exhibited stepwise decrements in the mRNAs of HMG CoA reductase and the low density lipoprotein receptor, two key cholesterol homeostatic genes. This was paralleled by decreased amounts of RNA polymerase II and the transcription factor SREBP1/2 at the reductase and lipoprotein receptor gene loci as measured by chromatin immunoprecipitation. Our study shows that the early phase of mouse growth can profoundly alter renal susceptibility to diverse forms of experimental acute renal injury. Mice have become the most widely used animal species for the studies of experimental acute renal failure (ARF). This is due to their relatively low cost, the great variety of strains±genetic modifications that are available, and the wide range of molecular probes (for example, monoclonal antibodies) that permit the study of specific injury pathways. Relatively young mice (2–4 months of age) are most commonly used, presumably because short periods of vivarium housing mitigate time constraints and expense. During the first 4 months of age, mice undergo rapid growth and development. For example, widely used CD-1 mice approximately triple their body weight from 3 to 16 weeks of age. It has previously been demonstrated that as rodents advance from adulthood into old age (for example, from ∼6 months to ∼2 years), increasing susceptibility to ischemic ARF results.1.Miura K. Goldstein R.S. Morgan D.G. et al.Age-related differences in susceptibility to renal ischemia in rats.Toxicol Appl Pharmacol. 1987; 87: 284-296Crossref PubMed Scopus (40) Google Scholar,2.Zager R.A. Alpers C.E. Effects of aging on expression of ischemic acute renal failure in rats.Lab Invest. 1989; 61: 290-294PubMed Google Scholar,3.Sabbatini M. Pisani A. Uccello F. et al.Atorvastatin improves the course of ischemic acute renal failure in aging rats.J Am Soc Nephrol. 2004; 15: 901-909Crossref PubMed Scopus (65) Google Scholar,4.Qiao X. Chen X. Wu D. et al.Mitochondrial pathway is responsible for aging-related increase of tubular cell apoptosis in renal ischemia/reperfusion injury.J Gerontol A Biol Sci Med Sci. 2005; 60: 830-839Crossref PubMed Scopus (57) Google Scholar,5.Chen G. Bridenbaugh E.A. Akintola A.D. et al.Increased susceptibility of aging kidney to ischemic injury: identification of candidate genes changed during aging, but corrected by caloric restriction.Am J Physiol. 2007; 293: F1272-F1281Crossref PubMed Scopus (55) Google Scholar,6.Miyaji T. Hu X. Yuen P.S. et al.Ethyl pyruvate decreases sepsis-induced acute renal failure and multiple organ damage in aged mice.Kidney Int. 2003; 64: 1620-1631Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar This may arise from a progressive loss of renal functional reserve, and possible aging-induced renal biochemical changes. In contrast, the potential impact of the early growth period (for example, the first 1–4 months of life) on renal susceptibility to injury has not been well defined. Hence, this study was conducted as an initial exploration of this issue. Between 3 and 16 weeks of age, the employed CD-1 mice manifested rapid growth, with an approximate tripling of body weight (Figure 1, left panel). This is consistent with data from the animal supplier (Charles River Laboratories, Wilmington, MA, USA). A proportionate increase in kidney mass was observed, as denoted by a near constant relationship between single kidney vs total body weight (∼0.65%; Figure 1, right panel). To test whether susceptibility to ARF is altered during this time frame, the mice were categorized as being ‘juvenile’ (age 3–4 weeks), ‘adolescent’ (5–6 weeks), or ‘mature’ (10–16 weeks) and challenged with intravenous endotoxin (lipopolysaccharide; Zager et al.7.Zager R.A. Johnson A.C. Lund S. et al.Levosimendan protects against experimental endotoxemic acute renal failure.Am J Physiol. 2006; 290: F1453-F1462Crossref PubMed Scopus (103) Google Scholar), intramuscular glycerol,8.Nath K.A. Balla G. Vercellotti G.M. et al.Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat.J Clin Invest. 1992; 90: 267-270Crossref PubMed Scopus (576) Google Scholar,9.Tracz M.J. Juncos J.P. Grande J.P. et al.Renal hemodynamic, inflammatory, and apoptotic responses to lipopolysaccharide in HO-1−/− mice.Am J Pathol. 2007; 170: 1820-1830Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,10.Zager R.A. Combined mannitol and deferoxamine therapy for myohemoglobinuric renal injury and oxidant tubular stress. Mechanistic and therapeutic implications.J Clin Invest. 1992; 90: 711-719Crossref PubMed Scopus (115) Google Scholar or intraperitoneal maleate11.Kellerman P.S. Exogenous adenosine triphosphate (ATP) preserves proximal tubule microfilament structure and function in vivo in a maleic acid model of ATP depletion.J Clin Invest. 1993; 92: 1940-1949Crossref PubMed Scopus (31) Google Scholar,12.Zager R.A. Johnson A.C. Naito M. et al.Maleate nephrotoxicity: mechanisms of injury and correlates with ischemic/hypoxic tubular cell death.Am J Physiol. 2008; 294: F187-F197Crossref PubMed Scopus (43) Google Scholar,13.Pacanis A. Strzelecki T. Rogliski J. Effects of maleate on the content of CoA and its derivatives in rat kidney mitochondria.J Biol Chem. 1981; 256: 13035-13038PubMed Google Scholar injection. These three ARF models were chosen for study because they induce renal injury by highly divergent mechanisms. Endotoxemia causes a predominantly hemodynamic form of ARF,7.Zager R.A. Johnson A.C. Lund S. et al.Levosimendan protects against experimental endotoxemic acute renal failure.Am J Physiol. 2006; 290: F1453-F1462Crossref PubMed Scopus (103) Google Scholar,14.Wang W. Zolty E. Falk S. et al.Endotoxemia-related acute kidney injury in transgenic mice with endothelial overexpression of GTP cyclohydrolase-1.Am J Physiol. 2008; 294: F571-F576Google Scholar,15.Wang W. Falk S.A. Jittikanont S. et al.Protective effect of renal denervation on normotensive endotoxemia-induced acute renal failure in mice.Am J Physiol. 2003; 283: F583-F587Google Scholar as evidenced by renal vasoconstriction, but maintenance of essentially normal renal histology (for example, Zager et al.7.Zager R.A. Johnson A.C. Lund S. et al.Levosimendan protects against experimental endotoxemic acute renal failure.Am J Physiol. 2006; 290: F1453-F1462Crossref PubMed Scopus (103) Google Scholar). As shown in Figure 2 (left panel), the severity of lipopolysaccharide-induced ARF directly correlated with animal age/weight, as assessed either by relative degrees of azotemia for the three age groups (P<0.001) or by the overall correlation coefficients between individual mouse weights vs blood urea nitrogen (BUN) concentrations. In contrast to lipopolysaccharide, glycerol evokes a structural form of ARF, as denoted by proximal tubule necrosis and heme protein cast formation.8.Nath K.A. Balla G. Vercellotti G.M. et al.Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat.J Clin Invest. 1992; 90: 267-270Crossref PubMed Scopus (576) Google Scholar,9.Tracz M.J. Juncos J.P. Grande J.P. et al.Renal hemodynamic, inflammatory, and apoptotic responses to lipopolysaccharide in HO-1−/− mice.Am J Pathol. 2007; 170: 1820-1830Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,10.Zager R.A. Combined mannitol and deferoxamine therapy for myohemoglobinuric renal injury and oxidant tubular stress. Mechanistic and therapeutic implications.J Clin Invest. 1992; 90: 711-719Crossref PubMed Scopus (115) Google Scholar This results from glycerol-induced rhabdomyolysis and hemolysis, with subsequent heme iron-driven proximal tubule oxidative stress.8.Nath K.A. Balla G. Vercellotti G.M. et al.Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat.J Clin Invest. 1992; 90: 267-270Crossref PubMed Scopus (576) Google Scholar,9.Tracz M.J. Juncos J.P. Grande J.P. et al.Renal hemodynamic, inflammatory, and apoptotic responses to lipopolysaccharide in HO-1−/− mice.Am J Pathol. 2007; 170: 1820-1830Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,10.Zager R.A. Combined mannitol and deferoxamine therapy for myohemoglobinuric renal injury and oxidant tubular stress. Mechanistic and therapeutic implications.J Clin Invest. 1992; 90: 711-719Crossref PubMed Scopus (115) Google Scholar Again, a striking correlation between age/body weight and the severity of ARF was observed, whether injury severity was assessed functionally (BUN, Figure 2) or by renal histology (Figure 3). In contrast to glycerol and lipopolysaccharide, which induce both extrarenal and renal injury, maleate toxicity is specific for the proximal tubule.12.Zager R.A. Johnson A.C. Naito M. et al.Maleate nephrotoxicity: mechanisms of injury and correlates with ischemic/hypoxic tubular cell death.Am J Physiol. 2008; 294: F187-F197Crossref PubMed Scopus (43) Google Scholar,13.Pacanis A. Strzelecki T. Rogliski J. Effects of maleate on the content of CoA and its derivatives in rat kidney mitochondria.J Biol Chem. 1981; 256: 13035-13038PubMed Google Scholar,16.Kaler G.M. Truong D.M. Khandelwal A. et al.Structural variation governs substrate specificity for organic anion transporter (OAT) homologs.J Biol Chem. 2007; 282: 23841-23853Crossref PubMed Scopus (68) Google Scholar This is due to the selective maleate transport/uptake by this nephron segment.11.Kellerman P.S. Exogenous adenosine triphosphate (ATP) preserves proximal tubule microfilament structure and function in vivo in a maleic acid model of ATP depletion.J Clin Invest. 1993; 92: 1940-1949Crossref PubMed Scopus (31) Google Scholar,16.Kaler G.M. Truong D.M. Khandelwal A. et al.Structural variation governs substrate specificity for organic anion transporter (OAT) homologs.J Biol Chem. 2007; 282: 23841-23853Crossref PubMed Scopus (68) Google Scholar With subsequent intracellular metabolism,13.Pacanis A. Strzelecki T. Rogliski J. Effects of maleate on the content of CoA and its derivatives in rat kidney mitochondria.J Biol Chem. 1981; 256: 13035-13038PubMed Google Scholar toxic intermediaries result producing mitochondrial dysfunction and a profound ATP depletion state. This culminates in a form of injury that recapitulates most critical features of post-ischemic ARF.12.Zager R.A. Johnson A.C. Naito M. et al.Maleate nephrotoxicity: mechanisms of injury and correlates with ischemic/hypoxic tubular cell death.Am J Physiol. 2008; 294: F187-F197Crossref PubMed Scopus (43) Google Scholar Using this maleate model, a striking direct relationship between animal weight/age and the severity of ARF was again observed, as gauged by BUN (Figure 2) and renal histology (Figure 3). It is notable that the greatest variation in renal injury with each of the three ARF models was found in the ‘adolescent’ age group (for example, BUN coefficients of variation as high as 65%). This implies that it is during this intermediate time frame that the most profound transition from an ‘injury-resistant’ to an ‘injury-sensitive’ phenotype occurs. Finally, it is notable that increasing either the maleate or glycerol dosages in ‘juvenile’ mice failed to induce the same degree of injury that was observed in ‘mature’ mice with lesser toxin doses (Figure 4). This underscores the relative degree of protection that the youngest mice express. Finally, although this study used male CD-1 mice, we have observed comparable degrees of protection in young female mice, and this correlates with body weight. Thus, the above-described results do not appear to be gender specific.Figure 2Severity of ARF for the three age groups, as assessed by BUN concentrations. With each of three ARF models, the severity of renal dysfunction increased with advancing age. The P-values compare the youngest vs the oldest groups, whereas the r values reflect the overall correlation coefficients between individual body weights and BUN concentrations for each ARF model (n=6–10 mice per group). Baseline BUN concentrations were 25±2 mg per 100 ml and did not significantly differ between the groups.View Large Image Figure ViewerDownload (PPT)Figure 3Renal histology. Examples of renal histology obtained from mice in the ‘juvenile’ vs the ‘mature’ mouse groups that were subjected to the maleate (a, b) or glycerol (c, d) model. Maleate-treated ‘juvenile’ mice maintained essentially normal histology (a). Conversely, fulminant tubular necrosis with cast formation was observed in the ‘mature’ group subjected to maleate injection (b). Glycerol had a minimal effect on renal histology in ‘juvenile’ mice (c). However, glycerol induced marked tubular necrosis and cast formation when administered to ‘mature’ mice (d).View Large Image Figure ViewerDownload (PPT)Figure 4Effects of increasing maleate and glycerol dosages in ‘juvenile’ mice on the severity of ARF. (left panel) Increasing maleate from 600 to 800 mg/kg failed to induce azotemia in ‘juvenile’ mice. At 1000 mg/kg, toxicity was apparent, but it was significantly less than that observed in ‘mature’ mice at a 600 mg/kg maleate dosage. (right panel) Increasing glycerol dosage from 9 to 12 mg/kg in ‘juvenile’ mice induced azotemia, but it was significantly less than that observed in ‘mature’ mice (n=5–10 per group).View Large Image Figure ViewerDownload (PPT) The explanation for the profound impact of rapid mouse growth/development on ARF susceptibility remains unknown, but it undoubtedly represents a fertile avenue for future study. It is almost certainly multifactorial in nature, and may well operate via different pathways in different ARF models. In an attempt to demonstrate that the rapid growth phase can, in fact, alter the expression of specific injury-modifying molecules, we sought age-dependent differences in the expression of renal cholesterol, a previously well-documented renal cytoprotectant.17.Zager R.A. Burkhart K.M. Johnson A.C. et al.Increased proximal tubular cholesterol content: implications for cell injury and ‘acquired cytoresistance’.Kidney Int. 1999; 56: 1788-1797Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar,18.Zager R.A. Plasma membrane cholesterol: a critical determinant of cellular energetics and tubular resistance to attack.Kidney Int. 2000; 58: 193-205Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,19.Banker D.E. Mayer S.J. Li H.Y. et al.Cholesterol synthesis and import contribute to protective cholesterol increments in acute myeloid leukemia cells.Blood. 2004; 104: 1816-1824Crossref PubMed Scopus (70) Google Scholar,20.Zager R.A. Johnson A.C. Hanson S.Y. Sepsis syndrome stimulates proximal tubule cholesterol synthesis and suppresses the SR-B1 cholesterol transporter.Kidney Int. 2003; 63: 123-133Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar In the aftermath of acute tubular injury, cellular cholesterol levels rise. This stabilizes the plasma membrane, and hence, prevents plasma membrane rupture during superimposed toxic or ischemic stress.17.Zager R.A. Burkhart K.M. Johnson A.C. et al.Increased proximal tubular cholesterol content: implications for cell injury and ‘acquired cytoresistance’.Kidney Int. 1999; 56: 1788-1797Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar,18.Zager R.A. Plasma membrane cholesterol: a critical determinant of cellular energetics and tubular resistance to attack.Kidney Int. 2000; 58: 193-205Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,19.Banker D.E. Mayer S.J. Li H.Y. et al.Cholesterol synthesis and import contribute to protective cholesterol increments in acute myeloid leukemia cells.Blood. 2004; 104: 1816-1824Crossref PubMed Scopus (70) Google Scholar,20.Zager R.A. Johnson A.C. Hanson S.Y. Sepsis syndrome stimulates proximal tubule cholesterol synthesis and suppresses the SR-B1 cholesterol transporter.Kidney Int. 2003; 63: 123-133Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Therefore, we questioned whether the highest renal cholesterol levels might be observed in the youngest mice, with progressive age-related reductions thereafter. Indeed, as shown in Figure 5 (left panel), this was the case. Renal tubular cholesterol content primarily reflects de novo HMG (3-hydroxy-3-methylglutaryl) CoA reductase (HMGCR)-driven synthesis, and low-density lipoprotein receptor (LDL-R)-mediated cholesterol extraction from plasma.17.Zager R.A. Burkhart K.M. Johnson A.C. et al.Increased proximal tubular cholesterol content: implications for cell injury and ‘acquired cytoresistance’.Kidney Int. 1999; 56: 1788-1797Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar,18.Zager R.A. Plasma membrane cholesterol: a critical determinant of cellular energetics and tubular resistance to attack.Kidney Int. 2000; 58: 193-205Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,19.Banker D.E. Mayer S.J. Li H.Y. et al.Cholesterol synthesis and import contribute to protective cholesterol increments in acute myeloid leukemia cells.Blood. 2004; 104: 1816-1824Crossref PubMed Scopus (70) Google Scholar,20.Zager R.A. Johnson A.C. Hanson S.Y. Sepsis syndrome stimulates proximal tubule cholesterol synthesis and suppresses the SR-B1 cholesterol transporter.Kidney Int. 2003; 63: 123-133Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar To assess whether, or which, of these pathways might be operative, we measured HMGCR mRNA and LDL-R mRNA levels during the studied growth period. As shown in Figure 6, both HMGCR and LDL-R mRNAs progressively decreased with advancing age, paralleling the reductions in cholesterol content. This suggests that both synthetic and uptake pathways may contribute to the observed age-dependent differences in renal cholesterol content. Notably, serum cholesterol progressively increased with age despite decreasing renal cholesterol levels (Figure 5, right panel). Although by no means conclusive, this reciprocal relationship between renal and serum cholesterol levels would be consistent with increased LDL-R-mediated cholesterol extraction from blood, and thereby, rising renal cholesterol levels.Figure 6mRNA levels of HMG CoA reductase (HMGCR) and low-density lipoprotein receptor (LDL-R) in renal cortex in ‘juvenile,’ ‘adolescent,’ and ‘mature’ mice. Both HMGCR and LDL-R mRNAs manifested a stepwise decline with age (n=5–6 per group).View Large Image Figure ViewerDownload (PPT) To test whether the above-noted changes in HMGCR mRNA and LDL-R mRNA levels reflected differences in gene transcription, rather than simply a potential difference in mRNA stabilities, we measured RNA polymerase II (Pol II) densities at the start and end exons of the HMGCR and LDL-R genes by microplate-based matrix chromatin immunoprecipitation (ChIP) technology (see Materials and Methods). Notably, Pol II density is both a mediator of and a surrogate marker for rates of gene transcription.21.Kornberg R.D. The molecular basis of eukaryotic transcription.Proc Natl Acad Sci USA. 2007; 104: 12955-12961Crossref PubMed Scopus (262) Google Scholar,22.Li B. Carey M. Workman J.L. The role of chromatin during transcription.Cell. 2007; 128: 707-719Abstract Full Text Full Text PDF PubMed Scopus (2466) Google Scholar,23.Thomas M.C. Chiang C.M. The general transcription machinery and general cofactors.Crit Rev Biochem Mol Biol. 2006; 41: 105-178Crossref PubMed Scopus (569) Google Scholar Indeed, at both start and end HMGCR and LDL-R gene exons, Pol II expression decreased with advancing age, thereby paralleling the observed mRNA and cholesterol declines (Figure 7). To further assess whether age-dependent differences in renal cholesterol content are reflected by differences in gene regulation, densities of Pol II, SREBP-1, and SREBP-2 (sterol regulatory element-binding protein transcription factors 1, 2; Thewke et al.24.Thewke D. Kramer M. Sinensky M.S. Transcriptional homeostatic control of membrane lipid composition.Biochem Biophys Res Commun. 2000; 273: 1-4Crossref PubMed Scopus (38) Google Scholar and Edwards et al.25.Edwards P.A. Tabor D. Kast H.R. et al.Regulation of gene expression by SREBP and SCAP.Biochim Biophys Acta. 2000; 1529: 103-113Crossref PubMed Scopus (250) Google Scholar) at two sites within the HMGCR promoter were assessed. Again consistent with the mRNA data, the youngest mice had the highest amounts of Pol II, SREBP-1, and SREBP-2 at the HMGCR promoter (Figure 8). The fact that Pol II and SREBP densities at silent genes (rDNA, β globin) did not vary according to age (Figure 9) indicates the specificity of the above-noted Pol II/SREBP results. Thus, the entire assessed HMGCR cholesterol synthetic axis (from ↑ transcription factors at the promoter → ↑ Pol II at the promoter → ↑ Pol II along the gene → ↑ mRNA → ↑ cholesterol) was relatively overexpressed in the ‘juvenile’ vs the ‘mature’ animals. Of even broader significance than these specific findings, the Pol II and SREBP data underscore the great potential utility of matrix ChIP assay for studying in vivo genomic and, potentially, epigenomic events in in vivo renal tissue.Figure 8Pol II, SREBP-1, and SREBP-2 at the HMGCR promoter region in ‘juvenile’ and ‘mature’ mice. Pol II was measured at two sites within the promoter (−100 and −400 base pairs, bp, from 5′-end to transcription start site, TSS), whereas the SREBPs were measured only at the -100 bp region. The amount of Pol II and both SREBPs were ∼2–3 × higher in the younger mouse kidneys (n=6 for each).View Large Image Figure ViewerDownload (PPT)Figure 9‘Negative’ controls for Pol II and SREBP recruitment. (left panel) Pol II levels were assessed at ribosomal DNA (rDNA) and there was no difference between the ‘juvenile’ and ‘mature’ groups. (right panel) The amounts of both SREBPs at a ‘silent’ (β globin) gene were equal for both mouse groups (n=6 determinations for each).View Large Image Figure ViewerDownload (PPT) Finally, we emphasize that we do not conclude that the cholesterol pathway is responsible for the age-dependent differences in ARF susceptibility noted in this study. Rather, the age-dependent changes within the cholesterol axis simply illustrate the dynamic nature of cellular processes that are in flux during early growth and development. Undoubtedly, changing levels of many other injury modifiers, such as growth factors (for example, epidermal growth factor, insulin like growth factor and hepatic growth factor), cell-cycle regulatory proteins (for example, p21), and potent cytoprotective molecules (for example, heme oxygenase-1) could also be in flux during 1–4 months of age. In light of these theoretical considerations, and the results of the present study, it would appear that great attention needs to be paid to mouse age when conducting studies of this type. Finally, the present study indicates that matrix ChIP assay is a powerful new tool that can be applied to the study of such issues. All experiments were conducted using male CD-1 mice (Charles River Laboratories) that were obtained at either 2–3 weeks (weight ∼17 g) or 4–5 weeks (weight ∼25 g) of age. They were maintained under routine vivarium conditions with free food and water access. They were arbitrarily assigned to one of the three age groups: ‘juvenile’, 3–4 weeks, ∼20 g; ‘adolescent’, 5–6 weeks, ∼30 g; or ‘mature’, 10–16 weeks, ∼40 g). The ‘mature’ group consisted of mice that were obtained either at 2–3 weeks or at 4–5 weeks of age and allowed to mature in this institution's vivarium. Because the age and weight of the mice represented a continuum within and between groups (rather than fixed arbitrary values), the results from the ARF experiments were compared between both the arbitrary groups and as overall correlations between age/weight vs the severity of ARF (as gauged by BUN concentrations). The following three ARF models were used: (1) an Escherichia coli endotoxemic model of ARF (2 mg/kg via tail vein injection; Zager et al.7.Zager R.A. Johnson A.C. Lund S. et al.Levosimendan protects against experimental endotoxemic acute renal failure.Am J Physiol. 2006; 290: F1453-F1462Crossref PubMed Scopus (103) Google Scholar); Na maleate nephrotoxicity (600 mg/kg, i.p.; Zager et al.12.Zager R.A. Johnson A.C. Naito M. et al.Maleate nephrotoxicity: mechanisms of injury and correlates with ischemic/hypoxic tubular cell death.Am J Physiol. 2008; 294: F187-F197Crossref PubMed Scopus (43) Google Scholar); and (3) glycerol-induced ARF (50% solution; 9 ml/kg, administered in a divided intramuscular dose in each hindlimb; Zager10.Zager R.A. Combined mannitol and deferoxamine therapy for myohemoglobinuric renal injury and oxidant tubular stress. Mechanistic and therapeutic implications.J Clin Invest. 1992; 90: 711-719Crossref PubMed Scopus (115) Google Scholar). Approximately 18–20 h after injections, the mice were anesthetized with pentobarbital (40–50 mg/kg, i.p.), a serum sample was obtained from the vena cava for BUN analysis, and the kidneys were resected and prepared for ChIP and mRNA analyses. Kidneys from the ‘juvenile’ and ‘mature’ mouse groups that underwent the maleate or glycerol challenges were cut longitudinally, fixed in 10% buffered formalin, 4 μm sections were cut and stained (hematoxylin and eosin, H&E), and examined by light microscopy to evaluate the extent of injury (tubular necrosis, cast formation). The following baseline parameters for the mice in different age groups were assessed: (1) single kidney weight (given as percentage (%) of total body weight); (2) BUN concentrations; (3) renal cortical mRNAs for HMGCR and LDL-R (reverse transcription-PCR; Zager et al.20.Zager R.A. Johnson A.C. Hanson S.Y. Sepsis syndrome stimulates proximal tubule cholesterol synthesis and suppresses the SR-B1 cholesterol transporter.Kidney Int. 2003; 63: 123-133Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, Zager and Kalhorn26.Zager R.A. Kalhorn T.F. Changes in free and esterified cholesterol: hallmarks of acute renal tubular injury and acquired cytoresistance.Am J Pathol. 2000; 157: 1007-1016Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, and Zager et al.27.Zager R.A. Johnson A.C. Hanson S.Y. et al.Acute tubular injury causes dysregulation of cellular cholesterol transport proteins.Am J Pathol. 2003; 163: 313-320Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar,28.Zager R.A. Johnson A.C. Hanson S.Y. Parenteral iron therapy exacerbates experimental sepsis.Kidney Int. 2004; 65: 2108-2112Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar); (4) renal cortical cholesterol content (gas chromatography; Zager and Kalhorn26.Zager R.A. Kalhorn T.F. Changes in free and esterified cholesterol: hallmarks of acute renal tubular injury and acquired cytoresistance.Am J Pathol. 2000; 157: 1007-1016Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar); (5) RNA Pol II density at the start and end exons of the HMGCR and LDL-R gene (tissues prepared as per Naito et al.29.Naito M. Bomsztyk K. Zager R.A. Endotoxin mediated RNA polymerase II recruitment to target genes in acute renal failure.J Am Soc Nephrol. 2008Google Scholar, and assayed by microplate-based matrix ChIP assay30.Flanagin S. Nelson J.D. Castner D.G. et al.Microplate-based chromatin immunoprecipitation method, matrix ChIP: a platform to study signaling of complex genomic events.Nucleic Acids Res. 2008; 36: e17Crossref PubMed Scopus (60) Google Scholar); (6) Pol II density at the HMGCR promoter (−100 and −400 bp; 5′-end to transcription start site); (7) SREBP-1 and SREBP-2 (transcription factors) at the HMGCR promoter (−100 bp); and (8) ‘negative controls’: Pol II at 18S ribosomal DNA (rDNA; Flanagin et al.30.Flanagin S. Nelson J.D. Castner D.G. et al.Microplate-based chromatin immunoprecipitation method, matrix ChIP: a platform to study signaling of complex genomic events.Nucleic Acids Res. 2008; 36: e17Crossref PubMed Scopus (60) Google Scholar); SREBP-1 and SREBP-2 at a ‘silent’ kidney gene (β globin). ChIP DNA data were expressed as a fraction of input DNA.30.Flanagin S. Nelson J.D. Castner D.G. et al.Microplate-based chromatin immunoprecipitation method, matrix ChIP: a platform to study signaling of complex genomic events.Nucleic Acids Res. 2008; 36: e17Crossref PubMed Scopus (60) Google Scholar All values were given as means±1 s.e.m. Statistical analyses were performed either by unpaired Student's t-testing for analyzing two sets of data, by analysis of variance if multiple groups were compared (after testing by Student's t-test with Bonferroni correction), and by calculating correlation coefficients. All the authors declared no competing interest. This work was supported by research grants from the National Institutes of Health (DK-R37-38431; DK-68520 (R.A.Z.); DK-R37-45978 and GM45134 (K.B.))." @default.
• W2010438778 created "2016-06-24" @default.
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• W2010438778 date "2008-09-01" @default.
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• W2010438778 title "Growth and development alter susceptibility to acute renal injury" @default.
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