Biology subjects

Amioka, N.

Publications and source records attributed to Amioka, N..

4 recordsLinked to original sources

bioRxiv2024

Renal Proximal Tubule Cell-specific Megalin Deletion Induces Tubulointerstitial Nephritis in Mice Fed Western Diet

BackgroundPharmacological inhibition of megalin (also known as low-density lipoprotein receptor-related protein 2: LRP2) attenuates atherosclerosis in hypercholesterolemic mice. Since megalin is abundant in renal proximal tubule cells (PTCs), the purpose of this study was to determine whether PTC-specific deletion of megalin reduces hypercholesterolemia-induced atherosclerosis in mice. MethodsFemale Lrp2 f/f mice were bred with male Ndrg1-Cre ERT2 +/0 mice to develop PTC-LRP2 +/+ and -/- littermates. To study atherosclerosis, all mice were bred to an LDL receptor -/- background and fed a Western diet to induce atherosclerosis. ResultsPTC-specific megalin deletion did not attenuate atherosclerosis in LDL receptor -/- mice in either sex. Serendipitously, we discovered that PTC-specific megalin deletion led to interstitial infiltration of CD68+ cells and tubular atrophy. The pathology was only evident in male PTC-LRP2 -/- mice fed the Western diet, but not in mice fed a normal laboratory diet. Renal pathologies were also observed in male PTC-LRP2 -/- mice in an LDL receptor +/+ background fed the same Western diet, demonstrating that the renal pathologies were dependent on diet and not hypercholesterolemia. In contrast, female PTC-LRP2 -/- mice had no apparent renal pathologies. In vivo multiphoton microscopy demonstrated that PTC-specific megalin deletion dramatically diminished albumin accumulation in PTCs within 10 days of Western diet feeding. RNA sequencing analyses demonstrated the upregulation of inflammation-related pathways in kidney. ConclusionsPTC-specific megalin deletion does not affect atherosclerosis, but leads to tubulointerstitial nephritis in mice fed Western diet, with severe pathologies in male mice.

pathology↗

bioRxiv2023

β-aminopropionitrile Induces Distinct Pathologies in the Ascending and Descending Thoracic Aortic Regions of Young Mice

BACKGROUND{beta}-aminopropionitrile (BAPN) is a pharmacological inhibitor of lysyl oxidase and lysyl oxidase-like proteins. Administration of BAPN promotes aortopathies, although there is a paucity of data on experimental conditions to generate pathology. The objective of this study was to define experimental parameters and determine whether equivalent or variable aortopathies were generated throughout the aortic tree during BAPN administration in mice. METHODSBAPN was administered in drinking water for a period ranging from 1 to 12 weeks. The impacts of BAPN were first assessed with regard to dose, strain, age, and sex. BAPN-induced aortic pathological characterization was conducted using histology and immunostaining. To investigate the mechanistic basis of regional heterogeneity, ascending and descending thoracic aortas were harvested after one week of BAPN administration before the appearance of overt pathology. RESULTSBAPN-induced aortic rupture predominantly occurred or originated in the descending thoracic aorta in young C57BL/6J or N mice. No apparent differences were found between male and female mice. For mice surviving 12 weeks of BAPN administration, profound dilatation was consistently observed in the ascending region, while there were more heterogeneous changes in the descending thoracic region. Pathological features were distinct between the ascending and descending thoracic regions. Aortic pathology in the ascending region was characterized by luminal dilatation and elastic fiber disruption throughout the media. The descending thoracic region frequently had dissections with false lumen formation, collagen deposition, and remodeling of the wall surrounding the false lumen. Cells surrounding the false lumen were predominantly positive for -smooth muscle actin. One week of BAPN administration compromised contractile properties in both regions equivalently, and RNA sequencing did not show obvious differences between the two aortic regions in smooth muscle cell markers, cell proliferation markers, and extracellular components. CONCLUSIONSBAPN-induced pathologies show distinct, heterogeneous features within and between ascending and descending aortic regions in mice.

pathology↗

bioRxiv2023

Regional Heterogeneity of Aortic Histology and Transcriptomes in Young Cynomolgus Monkeys

BackgroundThe regional heterogeneity of vascular components and transcriptomes is an important determinant of aortic biology. This notion has been explored in multiple mouse studies. In the present study, we examined the regional heterogeneity of aortas in non-human primates. MethodsAortic samples were harvested from the ascending, descending, suprarenal, and infrarenal regions of young control monkeys and adult monkeys provided with high fructose for 3 years. The regional heterogeneity of aortic structure and transcriptomes was examined by histological and bulk RNA sequencing analyses. ResultsImmunostaining of CD31 and SMA revealed that endothelial and smooth muscle cells were distributed homogeneously across the aortic regions. In contrast, elastic fibers were less abundant and dispersed in the infrarenal aorta compared to other regions and associated with collagen deposition. Bulk RNA sequencing identified a distinct transcriptome related to the Notch signaling pathway in the infrarenal aorta with significantly increased NOTCH3 mRNA compared to other regions. Immunostaining revealed that NOTCH3 protein was increased in the media of the infrarenal aorta. The abundance of medial NOTCH3 was positively correlated with the dispersion of elastic fibers. Adult cynomolgus monkeys provided with high fructose displayed vascular wall remodeling, such as smooth muscle cell loss and elastic fiber disruption, predominantly in the infrarenal region. The correlation between NOTCH3 and elastic fiber dispersion was enhanced in these monkeys. ConclusionsAortas of young cynomolgus monkeys display regional heterogeneity of their transcriptome and the structure of elastin and collagens. Elastic fibers in the infrarenal aorta are dispersed along with upregulation of medial NOTCH3. HIGHLIGHTS- The present study determined the regional heterogeneity of aortas from cynomolgus monkeys. - Aortas of young cynomolgus monkeys displayed region-specific aortic structure and transcriptomes. - Elastic fibers were dispersed in the infrarenal aorta along with increased NOTCH3 abundance in the media. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/530901v2_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@164c52corg.highwire.dtl.DTLVardef@ccfda8org.highwire.dtl.DTLVardef@213064org.highwire.dtl.DTLVardef@f007c3_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2022

Functional Exploration of Conserved Sequences in the Distal Face of Angiotensinogen

BackgroundAngiotensinogen (AGT) is an essential component in the renin-angiotensin system. AGT has highly conserved sequences in the loop and {beta}-sheet regions among species; however, their functions have not been studied. MethodsAdeno-associated viral vector (AAV) serotype 2/8 encoding mouse AGT with mutations of conserved sequences in the loop (AAV.loop-Mut), {beta}-sheet (AAV.{beta}sheet-Mut), or both regions (AAV.loop/{beta}sheet-Mut) were injected into male hepatocyte-specific AGT deficient (hepAGT-/-) mice in an LDL receptor -/- background. AAV containing mouse wild-type AGT (AAV.mAGT) or a null vector (AAV.null) were used as controls. Two weeks after AAV administration, all mice were fed a Western diet for 12 weeks. To determine how AGT secretion is regulated in hepatocytes, AAVs containing the above mutations were transducted into HepG2 cells. ResultsIn hepAGT-/- mice infected with AAV.loop-Mut or {beta}sheet-Mut, plasma AGT concentrations, systolic blood pressure, and atherosclerosis were comparable to those in AAV.mAGT-infected mice. Surprisingly, plasma AGT concentrations, systolic blood pressure, and atherosclerotic lesion size in hepAGT-/- mice infected with AAV.loop/{beta}sheet-Mut were not different from mice infected with AAV.null. In contrast, hepatic Agt mRNA abundance was elevated to a comparable magnitude as AAV.mAGT-infected mice. Immunostaining showed that AGT protein was accumulated trol and AAV containing wild-type mouse AGT as a positive control. We have demonstra ted consistently in this and previous studies tht located in the endoplasmic reticulum. ConclusionsThe conserved sequences in either the loop or {beta}-sheet region individually have no effect on AGT regulation, but the conserved sequences in both regions synergistically contribute to the secretion of AGT from hepatocytes. HIGHLIGHTSO_LIThe loop and {beta}-sheet regions in the distal face of angiotensinogen (AGT) have highly conserved sequences across species. C_LIO_LIMutations on either the loop or {beta}-sheet regions do not affect plasma AGT concentrations, blood pressure, and atherosclerosis in hypercholesterolemic mice. C_LIO_LIThe conserved sequences in the loop and {beta}-sheet regions regulate the secretion of AGT from hepatocytes synergistically in vivo and in cultured cells. C_LI

molecular biology↗