A high-fat diet aggravates tubulointerstitial but not glomerular lesions in obese Zucker rats

A high-fat diet aggravates tubulointerstitial but not glomerular lesions in obese Zucker ratsBackgroundDespite a large body of evidence that manipulation of dietary fat alters glomerular lesions, reports regarding the effects of dietary fat on tubulointerstitial lesions are limited. Obese Zucker rats (OZR) spontaneously develop glomerular and tubulointerstitial lesions in association with hyperlipidemia. We sought to elucidate the effects of dietary fat on glomerular and tubulointerstitial lesions in OZR versus lean Zucker rats (LZR) and to assess the involvement of macrophages in the development of these lesions.MethodsWe fed LZR and OZR either a low- (1%) or high-fat (20%) diet. After 30 weeks of the specified diet, the creatinine clearance (CCr) and renal histology as well as plasma lipid concentrations were examined. For morphological evaluation, glomerular sclerosis (GSI) and tubulointerstitial indices (TII) were each determined by a point-counting method. Infiltrating macrophages were stained immunohistochemically using an avidin-biotin complex technique.ResultsThe high-fat diet increased the plasma low-density lipoprotein concentration in OZR. Both low- and high-fat OZR groups had higher GSI and TII than LZR receiving either diet. The high-fat diet aggravated TII but not GSI or CCr in OZR; conversely, high fat intake worsened GSI and CCr but not TII in LZR. Tubulointerstitial macrophages were most prominent in the high-fat OZR group, followed by the low-fat OZR group. Glomerular macrophages were similar in number in all groups.ConclusionsThe manipulation of dietary fat has diverse effects on the kidney. A high-fat diet aggravated macrophage-mediated tubulointerstitial lesions in OZR, whereas in LZR, the diet induced glomerulosclerosis

Comparative analysis of protocadherin-11 X-linked expression among postnatal rodents, non-human primates, and songbirds suggests its possible involvement in brain evolution.

BACKGROUND: Protocadherin-11 is a cell adhesion molecule of the cadherin superfamily. Since, only in humans, its paralog is found on the Y chromosome, it is expected that protocadherin-11X/Y plays some role in human brain evolution or sex differences. Recently, a genetic mutation of protocadherin-11X/Y was reported to be associated with a language development disorder. Here, we compared the expression of protocadherin-11 X-linked in developing postnatal brains of mouse (rodent) and common marmoset (non-human primate) to explore its possible involvement in mammalian brain evolution. We also investigated its expression in the Bengalese finch (songbird) to explore a possible function in animal vocalization and human language faculties. METHODOLOGY/PRINCIPAL FINDINGS: Protocadherin-11 X-linked was strongly expressed in the cerebral cortex, hippocampus, amygdala and brainstem. Comparative analysis between mice and marmosets revealed that in certain areas of marmoset brain, the expression was clearly enriched. In Bengalese finches, protocadherin-11 X-linked was expressed not only in nuclei of regions of the vocal production pathway and the tracheosyringeal hypoglossal nucleus, but also in areas homologous to the mammalian amygdala and hippocampus. In both marmosets and Bengalese finches, its expression in pallial vocal control areas was developmentally regulated, and no clear expression was seen in the dorsal striatum, indicating a similarity between songbirds and non-human primates. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the enriched expression of protocadherin-11 X-linked is involved in primate brain evolution and that some similarity exists between songbirds and primates regarding the neural basis for vocalization

Two-Step Regulation of Ad4BP/SF-1 Gene Transcription during Fetal Adrenal Development: Initiation by a Hox-Pbx1-Prep1 Complex and Maintenance via Autoregulation by Ad4BP/SF-1

The orphan nuclear receptor Ad4BP/SF-1 (adrenal 4 binding protein/steroidogenic factor 1) is essential for the proper development and function of reproductive and steroidogenic tissues. Although the expression of Ad4BP/SF-1 is specific for those tissues, the mechanisms underlying this tissue-specific expression remain unknown. In this study, we used transgenic mouse assays to examine the regulation of the tissue-specific expression of Ad4BP/SF-1. An investigation of the entire Ad4BP/SF-1 gene locus revealed a fetal adrenal enhancer (FAdE) in intron 4 containing highly conserved binding sites for Pbx-Prep, Pbx-Hox, and Ad4BP/SF-1. Transgenic assays revealed that the Ad4 sites, together with Ad4BP/SF-1, develop an autoregulatory loop and thereby maintain transcription, while the Pbx/Prep and Pbx/Hox sites initiate transcription prior to the establishment of the autoregulatory loop. Indeed, a limited number of Hox family members were found to be expressed in the adrenal primordia. Whether a true fetal-type adrenal cortex is present in mice remained controversial, and this argument was complicated by the postnatal development of the so-called X zone. Using transgenic mice with lacZ driven by the FAdE, we clearly identified a fetal adrenal cortex in mice, and the X zone is the fetal adrenal cells accumulated at the juxtamedullary region after birth

Transgenic Expression of Ad4BP/SF-1 in Fetal Adrenal Progenitor Cells Leads to Ectopic Adrenal Formation

Deficiency of adrenal 4 binding protein/steroidogenic factor 1 (Ad4BP/SF-1; NR5A1) impairs adrenal development in a dose-dependent manner, whereas overexpression of Ad4BP/SF-1 is associated with adrenocortical tumorigenesis. Despite its essential roles in adrenal development, the mechanism(s) by which Ad4BP/SF-1 regulates this process remain incompletely understood. We previously identified a fetal adrenal enhancer (FAdE) that stimulates Ad4BP/SF-1 expression in the fetal adrenal gland by a two-step mechanism in which homeobox proteins initiate Ad4BP/SF-1 expression, which then maintains FAdE activity in an autoregulatory loop. In the present study, we examined the effect of transgenic expression of Ad4BP/SF-1 controlled by FAdE on adrenal development. When Ad4BP/SF-1 was overexpressed using a FAdE-Ad4BP/SF-1 transgene, FAdE activity expanded outside of its normal field, resulting in increased adrenal size and the formation of ectopic adrenal tissue in the thorax. The increased size of the adrenal gland did not result from a corresponding increase in cell proliferation, suggesting rather that the increased levels of Ad4BP/SF-1 may divert uncommitted precursors to the steroidogenic lineage. The effects of FAdE-controlled Ad4BP/SF-1 overexpression in mice provide a novel model of ectopic adrenal formation that further supports the critical role of Ad4BP/SF-1 in the determination of steroidogenic cell fate in vivo

Generation of pulsatile ERK activity in mouse embryonic stem cells is regulated by Raf activity

Abstract The extracellular signal-regulated kinase (ERK) is a serine/threonine kinase that is known to regulate cellular events such as cell proliferation and differentiation. The ERK signaling pathway is activated by fibroblast growth factors, and is considered to be indispensable for the differentiation of primitive endoderm cells, not only in mouse preimplantation embryos, but also in embryonic stem cell (ESC) culture. To monitor ERK activity in living undifferentiated and differentiating ESCs, we established EKAREV-NLS-EB5 ESC lines that stably express EKAREV-NLS, a biosensor based on the principle of fluorescence resonance energy transfer. Using EKAREV-NLS-EB5, we found that ERK activity exhibited pulsatile dynamics. ESCs were classified into two groups: active cells showing high-frequency ERK pulses, and inactive cells demonstrating no detectable ERK pulses during live imaging. Pharmacological inhibition of major components in the ERK signaling pathway revealed that Raf plays an important role in determining the pattern of ERK pulses

Pcdh11X expression in the cortico-striatal pathway of the marmoset brain.

<p>GP at P0 (A) and adult stage (B); VA at P2 (C), and adult stage (D); STh at P2 (E), and adult stage (F); SNr at P2 (G), and adult stage (H). Pcdh11X is weakly expressed in Cd and Pu at P0, but their expressions have disappeared by the adult stage. Scale bars represent 1 mm.</p

Strong Pcdh11X expression is seen in brain areas involved in memory and emotion.

<p>Pcdh11X expressions in BM (A–D) and AHi (E–H), in the CA3 region of the hippocampus (I–L), and the PrS (M–P) in the developing postnatal marmoset brain. Scale bars represent 500 µm (L), 1 mm (D, H), and 2 mm (M–P).</p

Pcdh11X expression in the auditory pathway of songbirds.

<p>Telencephalic auditory areas in P30 and adult birds (A, B). Clear Pcdh11X expression is seen in CM and NCM. As in marmosets and mice, no clear expression is seen in the auditory pathway outside the telencephalon (C, D, E), except for CN (F). L, Field L. Scale bars represent 1 mm (B) and 500 µm (C, E, F).</p