Project description:Aging is accompanied by a gradual loss of systemic metabolic homeostasis, which is maintained by multiple-organs, especially the kidney and kidney. However, a systematic study of the regulatory networks and regulatory transcription factors (TFs) of aging in the kidney and kidney remains lacking. Here, we performed an integrated analysis of multi-omics datasets in the kidney and kidney from young and aged mice, including RNA-seq, reduced representation bisulfite sequencing (RRBS) and ATAC-seq datasets, which indicated that enhanced inflammation and dysregulated metabolism were conserved signatures in aged kidney and kidney in both the transcriptome and epigenome. Transcription factor and regulatory network analysis indicated that activation of AP-1 and SPI1 was responsible for enhanced inflammation, and down-regulation of HNFs and PPARs contributed to dysregulated metabolism in aged kidney and kidney. Importantly, we found that the activation of AP-1 was cellular autonomous in aged hepatic and renal cells. However, enhanced SPI1 was caused by elevated infiltration of macrophages. Importantly, inhibition of AP-1 with small molecule combination attenuated inflammation phenotypes of aging in vivo and in vitro. Taken together, our analysis revealed common signatures and regulatory TFs of aging in the kidney and kidney, providing novel targets for the development of anti-aging interventions.
Project description:Chronic Kidney Disease (CKD), a global health burden, is strongly associated with age-related renal function decline, hypertension and diabetes, frequent consequences of obesity. Despite extensive studies the mechanisms determining susceptibility to CKD remain elusive. Clinical evidence together with prior studies from our group showed that perinatal metabolic disorders after maternal obesity adversely affect kidney structure and function throughout life. Since obesity and aging processes converge in similar pathways we tested if perinatal obesity induced by High-Fat Diet (HFD)-fed female mice sensitizes aging-associated mechanism in kidneys of newborn mice. Tissue from the kidney cortex and the kidney medulla was collected from offspring of control or HFD-fed mice.
Project description:Aging-related diseases and their comorbidities affect the life quality of a constantly growing proportion of our population. Age-associated changes of kidney structure and function are considerable contributors to the dramatically increased incidence of chronic kidney disease world-wide which has been identified to be a prominent cardiovascular risk factor. In order to detect molecular mechanisms involved in kidney aging we analyzed gene expression profiles of kidneys from adult and aged wild-type mice by a three-layered omics strategy. To this end, transcriptomic, proteomic and targeted lipidomic profiles of young and aged mice were generated and integrated. Transcriptome and proteome analyses revealed differential expression of genes involved primarily in lipid metabolism and immune response. Additional lipidomic analyses uncovered significant age-related differences in the total amount of phosphatidylethanolamines, phosphatidylcholines and sphingomyelins as well as in subspecies of phosphatidylserines and ceramides, while total ceramide levels remained unchanged. By integration of these datasets we identified Aldh1a1, a key enzyme in vitamin A metabolism specifically expressed in the medullary ascending limb, as one of the most prominent upregulated proteins in old kidneys. Moreover, ceramidase Asah1 was highly expressed in aged kidneys, consistent with a decrease in ceramide C16. In summary, our data suggest that changes in lipid metabolism are involved in the process of kidney aging and in the development of chronic kidney disease. 14 weeks females (4 replicates); 96 weeks females (5 replicates)
Project description:Total ribosome-depleted RNA sequencing was performed on the left cardiac ventricle, skeletal muscle (quadriceps femoris), and kidney of young adult (16.5 wk) and early aging (86 wk) C57BL/6J mice.
Project description:Transcriptional profiling of whole kidneys of adult Dot1lAC mice comparing control kidneys of their littermates Dot1lf/f mice fed a normal pellet Na+ diet. Goal was to determine the effects of inactivation of histone H3 K79 methyltransferase Dot1l in Aqp2-expressing cells in Dot1lAC on global kidney gene expression. Two-condition experiment, Dot1lAC vs. Dot1lf/f. Biological replicates: Total kidney RNAs from 4 mice/genotype were mixed within the same genotype.
Project description:During aging, the kidney undergoes functional and physiological changes that are closely affiliated with chronic kidney disease (CKD). There is increasing evidence supporting the role of lipid or lipid-derived mediators in the pathogenesis of CKD and other aging-related diseases. To understand the role of lipids in various metabolic processes during kidney aging, we conducted MALDI imaging mass spectrometry (MALDI-IMS) analysis in kidneys harvested from young (2 months old, n=3) and old mice (24 months old, n=3). MALDI-IMS analysis showed an increase in ceramide level and a decrease in sphingomyelin (SM) and phosphatidylcholine (PC) levels in kidneys of old mice. The increased expression of cPLA2 and SMPD1 protein in aged kidney was confirmed by immunohistochemistry and western blot analysis. Our MALDI-IMS data showed the altered distribution of lipids in aged kidney as indicative of aging-related functional changes of the kidney. Combined analysis of MALDI-IMS and IHC confirmed lipidomic changes and expression levels of responsible enzymes as well as morphological changes.