Identification of Messenger RNA Signatures in Age-Dependent Renal Impairment
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE249488 | GEO | 2023/12/11
REPOSITORIES: GEO
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Project description:Background: Age-dependent renal impairment contributes to renal dysfunction in both the general population and young and middle-aged patients with renal diseases. Pathological changes in age-dependent renal impairment include glomerulosclerosis and tubulointerstitial fibrosis. The molecules involved in age-dependent renal impairment are not fully elucidated. MicroRNA (miRNA) species were reported to modulate various renal diseases, but the miRNA species involved in age-dependent renal impairment are unclear. Here, we investigated miRNAs in age-dependent renal impairment, and we evaluated their potential as biomarkers and therapeutic targets. Methods: We conducted an initial microarray profiling analysis to screen miRNAs whose expression levels changed in kidneys of senescence-accelerated resistant (SAMR1)-10-week-old (wk) mice and SAMR1-50wk mice and senescence-accelerated prone (SAMP1)-10wk mice and SAMP1-50wk mice. We then evaluated the expressions of differentially expressed miRNAs in serum from 13 older patients (>65 years old) with age-dependent renal impairment (estimated glomerular filtration ratio <60 mL/min/1.73 m2) by a quantitative real-time polymerase chain reaction (qRT-PCR) and compared the expressions with those of age-matched subjects with normal renal function. We also administered miRNA mimics or inhibitors (5 nmol) with a nonviral vector (polyethylenimine nanoparticles: PEI-NPs) to SAMP1-20wk mice to investigate the therapeutic effects. Results: The qRT-PCR revealed a specific miRNA (miRNA-503-5p) whose level was significantly changed in SAMP1-50wk mouse kidneys in comparison to the controls. The expression level of miRNA-503-5p was upregulated in the serum of the 13 patients with age-dependent renal impairment compared to the age-matched subjects with normal renal function. The administration of a miRNA-503-5p-inhibitor with PEI-NPs decreased the miRNA-503-5p expression levels, resulting in the inhibition of renal fibrosis in mice via an inhibition of a pro-fibrotic signaling pathway and a suppression of glomerulosclerosis in mice by inhibiting intrinsic signaling pathways. Conclusion: miRNA-503-5p may represent a biomarker for age-dependent renal impairment, and the inhibition of miRNA-503-5p had no effect on age-dependent renal impairment. However, the inhibition of miRNA-503-5p had therapeutic effects on renal fibrosis and glomerulosclerosis.
2022-03-17 | GSE198741 | GEO
Project description:miRNAs in age-dependent renal impairment
| PRJNA816716 | ENA
Project description:A growing body of research shows that epigenetic mechanisms are critically involved in normal and pathological aging. The Senescence-Accelerated Mouse Prone 8 (SAMP8) can be considered an useful tool to better understand the dynamics of the global epigenetic landscape during the aging process since its phenotype is not fully explained by genetic factors. Here we investigated dysfunctional age-related transcriptional profiles and epigenetic programming enzymes in the hippocampus of 2- and 9-month-old SAMP8 female mice using the Senescent-Accelerated Resistant 1 (SAMR1) mouse strain as control. SAMP8 mice presented 1,062 genes dysregulated at 2 months of age, and 1,033 genes at 9 months, with 92 genes concurrently dysregulated at both ages in reference to age mated SAMR1. SAMP8 mice showed a significant decrease in global DNA methylation (5-mC) at 2 months while hydroxymethylation (5-hmC) levels were increased in SAMP8 mice at 2 and 9 months of age compared to SAMR1. These changes were accompanied by changes in the expression of several enzymes that regulate 5-mC and methylcytosine oxidation. Acetylated H3 and H4 histone levels were significantly diminished in SAMP8 mice at 2-month-old compared to SAMR1 and altered Histone DeACetylase (HDACs) profiles were detected in both young and old SAMP8 mice. We analyzed 84 different mouse miRNAs known to be altered in neurological diseases or involved in neuronal development. Compared with SAMR1, SAMP8 mice showed 28 and 17 miRNAs differentially expressed at 2 and 9 months of age, respectively, 6 of these miRNAs overlapped at both ages. We used several bioinformatic approaches to integrate our data in mRNA:miRNA regulatory networks and functional predictions for young and aged animals. In sum, our study reveals interplay between epigenetic mechanisms and gene networks that seems to be relevant for the progression towards a pathological aging and provides several potential markers and therapeutic candidates for Alzheimer’s Disease (AD) and age-related cognitive impairment.
2018-10-26 | GSE121769 | GEO
Project description:A growing body of research shows that epigenetic mechanisms are critically involved in normal and pathological aging. The Senescence-Accelerated Mouse Prone 8 (SAMP8) can be considered an useful tool to better understand the dynamics of the global epigenetic landscape during the aging process since its phenotype is not fully explained by genetic factors. Here we investigated dysfunctional age-related transcriptional profiles and epigenetic programming enzymes in the hippocampus of 2- and 9-month-old SAMP8 female mice using the Senescent-Accelerated Resistant 1 (SAMR1) mouse strain as control. SAMP8 mice presented 1,062 genes dysregulated at 2 months of age, and 1,033 genes at 9 months, with 92 genes concurrently dysregulated at both ages in reference to age mated SAMR1. SAMP8 mice showed a significant decrease in global DNA methylation (5-mC) at 2 months while hydroxymethylation (5-hmC) levels were increased in SAMP8 mice at 2 and 9 months of age compared to SAMR1. These changes were accompanied by changes in the expression of several enzymes that regulate 5-mC and methylcytosine oxidation. Acetylated H3 and H4 histone levels were significantly diminished in SAMP8 mice at 2-month-old compared to SAMR1 and altered Histone DeACetylase (HDACs) profiles were detected in both young and old SAMP8 mice. We analyzed 84 different mouse miRNAs known to be altered in neurological diseases or involved in neuronal development. Compared with SAMR1, SAMP8 mice showed 28 and 17 miRNAs differentially expressed at 2 and 9 months of age, respectively, 6 of these miRNAs overlapped at both ages. We used several bioinformatic approaches to integrate our data in mRNA:miRNA regulatory networks and functional predictions for young and aged animals. In sum, our study reveals interplay between epigenetic mechanisms and gene networks that seems to be relevant for the progression towards a pathological aging and provides several potential markers and therapeutic candidates for Alzheimer’s Disease (AD) and age-related cognitive impairment.
2018-10-26 | GSE121767 | GEO
Project description:SAMP8 mice serve as an accelerated aging model characterized by inflammation and neurological memory deficits, in contrast to their control SAMR1 counterparts. To investigate the role of microglia in aging, we conducted a comprehensive analysis of microglial heterogeneity using CITE-seq. CD11b positive cells were extracted from cerebellum and olfactory bulb-removed brains at key time points: 2 months, 5 months, and 9 months of age.
2024-05-29 | GSE253582 | GEO
Project description:OVE26 (OVE) mice provide a useful model of advanced diabetic nephropathy (DN) with respect to albuminuria and pathologies. We showed that albuminuria, reduced GFR and interstitial fibrosis, which normally take 8-9 months to develop, are more advanced in uninephrectomized OVE mice within 10 weeks of surgery, at 4.5 months of age. The accelerated progression of renal damage, especially renal fibrosis in OVE-uni mice, was also identified at the gene expression level. The hepatic fibrosis/hepatic stellate cell activation pathway was by far the most significant Ingenuity canonical pathway identified by gene array in OVE-uni mice. Many inflammatory- and immune-related pathways were found among the top pathways up-regulated in OVE-uni kidneys, including acute-phase response signaling, leukocyte extravasation, IL6, IL10, IL12 signaling, TREM1 signaling, dendritic cell maturation and the complement system. These pathways were also dramatically up-regulated in 8-month-old OVE mice (GSE20636). Nephrectomized OVE mice are a much faster alternative model for studying advanced renal disease in diabetes.
2011-04-15 | GSE21448 | GEO
Project description:Our present study reveals significant decelerating effects on senescence processes in middle-aged SAMP1 mice supplemented for 6 or 14 months with the reduced form (QH2, 500 mg/ kg BW/ day) of coenzyme Q10 (CoQ10). To unravel molecular mechanisms of these CoQ10 effects, a genome-wide transcript profiling in liver, heart, brain and kidney of SAMP1 mice supplemented with the reduced (QH2) or oxidized form of CoQ10 (Q10) was performed. Liver seems to be the main target tissue of CoQ10 intervention, followed by kidney, heart and brain. Stringent evaluation of the resulting data revealed that QH2 has a stronger impact on gene expression than Q10, which was primarily due to differences in the bioavailability. Indeed, we found that QH2 supplementation was more effective than Q10 to increase levels of CoQ10 in the liver of SAMP1 mice (54.92-fold and 30.36-fold, respectively). To identify functional and regulatory connections of the âtop 50â (p < 0.05) up- and down-regulated QH2-sensitive transcripts in liver (fold changes ranging from 21.24 to -6.12), text mining analysis (Genomatix BiblioSphere, GFG level B3) was used. Hereby, we identified 11 QH2-sensitive genes which are regulated by PPAR-α and are primarily involved in cholesterol synthesis (e.g. HMGCS1, HMGCL, HMGCR), fat assimilation (FABP5), lipoprotein metabolism (PLTP) and inflammation (STAT-1). Thus, we provide evidence that QH2 is involved in the reduction of fat and cholesterol synthesis via modulation of the PPAR-α signalling pathway. These data may explain, at least in part, the observed effects on decelerated age-dependent degeneration processes in QH2-supplemented SAMP1 mice. Whole genome expression profiles were analysed from liver, heart, brain and kidney (each analyzed separately) of SAMP1 mice supplemented with QH2, Q10 or a control diet. From every experimental group, three mice each were sacrificed 6 or 14 months after supplementation, resulting in a total of 72 microarrays.
2010-03-15 | E-GEOD-15129 | biostudies-arrayexpress
Project description:The early events that signal renal dysfunction in presymptomatic heart failure are unclear. To evaluate this, we performed RNA-seq on kidneys from transgenic mice with cardiac-specific overexpression of mutant alpha-B-crystallin, which develop slowly progressive cardiomyopathy. Presymptomatic transgenic mice display an increase in serum creatinine and in urinary neutrophil gelatinase-associated lipocalin (NGAL), but lack chronic interstitial fibrosis. Presymptomatic transgenic mouse kidneys exhibited a worsened response to ischemia-reperfusion injury based on serum creatinine, urine NGAL, tubule dilation and cast score, and apoptosis. Our findings demonstrate functional renal impairment, urinary biomarker elevations, and gene expression changes that occur in early presymptomatic heart failure, which dramatically increase the susceptibility to subsequent acute kidney injury.
2018-02-16 | GSE99703 | GEO
Project description:Congenital obstructive nephropathy is a common cause of chronic kidney disease and a leading indication for renal transplant in children. The cellular and molecular responses of the kidney to congenital obstruction are incompletely characterized. In this study, we evaluated global transcription in kidneys with graded hydronephrosis in the megabladder (mgb-/-) mouse to better understand the pathophysiology of congenital obstructive nephropathy. Three primary pathways associated with kidney remodeling/repair were induced in mgb-/- kidneys independent of the degree of hydronephrosis. These pathways included retinoid signaling, steroid hormone metabolism, and renal response to injury. Urothelial proliferation and the expression of genes with roles in the integrity and maintenance of the renal urothelium were selectively increased in mgb-/- kidneys. Ngal/Lcn2, a marker of acute kidney injury, was elevated in 36% of kidneys with higher grades of hydronephrosis. Evaluation of Ngalhigh versus Ngallow kidneys identified the expression of several novel candidate markers of renal injury. This study indicates that the development of progressive hydronephrosis in mgb-/- mice results in renal adaptation that includes significant changes in the morphology and potential functionality of the renal urothelium. These observations will permit the development of novel biomarkers and therapeutic approaches to progressive renal injury in the context of congenital obstruction. Gene expression was measured in control, mild, moderate and severely hydronephrotic megabladder mouse kidneys. A total of 6 control kidneys were compared to 18 mutant kidneys from age-matched male animals.
2013-06-18 | E-GEOD-48041 | biostudies-arrayexpress
Project description:OVE26 (OVE) mice provide a useful model of advanced diabetic nephropathy (DN) with respect to albuminuria and pathologies. We showed that albuminuria, reduced GFR and interstitial fibrosis, which normally take 8-9 months to develop, are more advanced in uninephrectomized OVE mice within 10 weeks of surgery, at 4.5 months of age. The accelerated progression of renal damage, especially renal fibrosis in OVE-uni mice, was also identified at the gene expression level. The hepatic fibrosis/hepatic stellate cell activation pathway was by far the most significant Ingenuity canonical pathway identified by gene array in OVE-uni mice. Many inflammatory- and immune-related pathways were found among the top pathways up-regulated in OVE-uni kidneys, including acute-phase response signaling, leukocyte extravasation, IL6, IL10, IL12 signaling, TREM1 signaling, dendritic cell maturation and the complement system. These pathways were also dramatically up-regulated in 8-month-old OVE mice (GSE20636). Nephrectomized OVE mice are a much faster alternative model for studying advanced renal disease in diabetes. Study of renal gene expression in diabetic OVE26 mice. Uninephrectomy was used as an accelerating factor. Pooled RNA samples from 4 individual mice in each treatment group (OVE-uni, OVE-sham, FVB-uni, FVB-sham) were used for probe hybridization. Treatment groups: OVE-uni: uninephrectomy treatment in diabetic mice OVE-sham: sham surgery treatment in diabetic mice FVB-uni: uninephrectomy treatment in nondiabetic mice FVB-sham: sham surgery treatment in nondiabetic mice
2011-04-15 | E-GEOD-21448 | biostudies-arrayexpress