Angiotensin II disrupts the cytoskeletal architecture of human urine-derived podocytes and results in activation of the renin-angiotensin system
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PROVIDER: PRJNA718845 | ENA |
REPOSITORIES: ENA
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Project description:High blood pressure is one of the major public health problems which causes severe disorders in several tissues including the human kidney. One of the most important signaling pathways associated with the regulation of blood pressure is the renin-angiotensin system (RAS), with its main mediator angiotensin II (ANGII). Elevated levels of circulating and intracellular ANGII and aldosterone lead to pro-fibrotic, -inflammatory and -hypertrophic milieu that causes remodelling and dysfunction in cardiovascular and renal tissues. Furthermore, ANGII has been recognized as major risk factor for the induction of apoptosis in podocytes, ultimately leading to chronic kidney disease (CKD). In the past, disease modeling of kidney-associated malignancies was extremely difficult, as the derivation of kidney originated cells is very challenging. Here we describe a differentiation protocol for reproducible differentiation of SIX2-positive urine derived renal progenitor cells (UdRPCs) into mature podocytes bearing typical foot processes. The UdRPCs-derived podocytes show the ability to execute Albumin endocytosis and the activation of the renin-angiotensin system by being responsive to ANGII stimulation. Our data reveals the ANGII dependent downregulation of NPHS1 and SYNPO, resulting in the disruption of the complex podocyte cytoskeletal architecture, as shown by immunofluorescence-based detection of α–ACTININ. In the present manuscript we confirm and propose UdRPCs as a unique cell type useful for studying nephrogenesis and associated diseases. Furthermore, the responsiveness of UdRPCs-derived podocytes to ANGII implies potential applications in nephrotoxicity studies and drug screening.
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2010-05-16 | E-GEOD-14687 | biostudies-arrayexpress
Project description:Regulated endocrine specific protein 18 (Resp18), expression has been specifically located in a series of tissues and cell types however the exact cellular function is unknown. In previous studies we have showed that a targeted disruption of Resp18 in Dahl SS rats (Resp18mutant) resulted in higher blood pressure (BP), increased renal fibrosis, and decreased survival rate on a long term (6-week) 2% high salt (HS) diet treatment compared with wild type SS rats. In the current study we studied whether a short term (1 week) exposure to HS diet shows a similar effect in Resp18mutant rats. Furthermore, previously we have shown that in addition to BP phenotype Resp18mutant rats have demonstrated deteriorative kidney phenotype evident through renal fibrosis, protein urea and protein cast formation. Based on this background we conducted BP study and performed transcriptomic profiling of the kidney after one-week exposure to HS diet treatment. Through radio-telemetry procedure, we found that the systolic BP was increased in the Resp18mutant rats compared with SS rats even with short term HS diet exposure. Therefore, we sought out to investigate if there was any alteration in the transcriptomic response by HS diet treatment in the Resp18mutant rat kidneys. Using RNA sequencing approach, we found that Resp18mutant rats showed a differential expression of 25 genes of which one was an upregulation of Ren. We confirmed the upregulation of Ren and other differentially expressed genes via qRT-PCR analysis. Upon KEGG pathway enrichment we found that the Resp18mutant rat showed upregulation in the renin angiotensin system (RAAS), and renin secretion pathway. Furthermore, the renin activity is found to be higher in Resp18mutant rats serum compared with SS rats. Therefore, these observations demonstrate that upon disruption of Resp18 gene in SS rats associated with the increase in renin secretion and thus increase BP.
2021-07-01 | GSE149006 | GEO
Project description:The postnatal development of the mouse is characterized by a stress hyporesponsive period (SHRP), where basal corticosterone levels are low and responsiveness to mild stressors is reduced. Maternal separation is able to disrupt the SHRP and is widely used to model early trauma. In this study we aimed at identifying of brain systems involved in acute and possible long-term effects of maternal separation. We conducted a microarray-based gene expression analysis in the hypothalamic paraventricular nucleus after maternal separation, which revealed 52 differently regulated genes compared to undisturbed controls, among them are 37 up-regulated and 15 down-regulated genes. One of the prominently unregulated genes, angiotensinogen, was validated using a in-situ hybridization. Angiotensinogen is the precursor of angiotensin II the main effector of the brain renin-angiotensin system (RAS), which is known to be involved in stress system modulation in adult animals. Using the selective angiotensin type I receptor (AT(1)) antagonist candesartan we found strong effects on CRH and GR mRNA expression in the brain and ACTH release following maternal separation. AT(1) receptor blockade appears to enhance central effects of maternal separation in the neonate, suggesting a suppressing function of brain RAS during the SHRP. Taken together, our results illustrate the molecular adaptations that occur in the paraventricular nucleus following maternal separation and identify signaling cascades, that control stress system activity in the neonate. Keywords: phenotype
2009-07-22 | GSE14687 | GEO
Project description:The placental renin-angiotensin system (RAS) is important for placentation. RAS expression is greatest in early gestation. This may be due (in part) to suppression of miRNAs that target the placental RAS, but this has never been explored. In this study, human placental miRNAs were measured at 10–11 (early), 14–18 (mid), and 38–40 (term) weeks gestation, as well as in placentae from women with early- or late-onset preeclampsia (n=4/group), using an Agilent miRNA microarray (V19). All miRNAs showed a gestational increase and could influence the transgestational profile of the human placental RAS. Additionally, on the array, three miRNAs predicted to target the RAS (miR-892c-3p, miR-378c and miR-514-3p ) were overexpressed in placentae of late-onset preeclamptic women.
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