Lymphangiogenesis is associated with chronic kidney disease (CKD) and occurs following kidney transplant. Here, we demonstrate that expanding lymphatic vessels (LVs) in kidneys and corresponding renal draining lymph nodes (RDLNs) play critical roles in promoting intrarenal inflammation and fibrosis following renal injury. Our studies show that lymphangiogenesis in the kidney and RDLN is driven by proliferation of preexisting lymphatic endothelium expressing the essential C-C chemokine ligand 21 (CCL21). New injury-induced LVs also express CCL21, stimulating recruitment of more CCR7+ dendritic cells (DCs) and lymphocytes into both RDLNs and spleen, resulting in a systemic lymphocyte expansion. Injury-induced intrarenal inflammation and fibrosis could be attenuated by blocking the recruitment of CCR7+ cells into RDLN and spleen or inhibiting lymphangiogenesis. Elucidating the role of lymphangiogenesis in promoting intrarenal inflammation and fibrosis provides a key insight that can facilitate the development of novel therapeutic strategies to prevent progression of CKD-associated fibrosis.
Acute kidney injury (AKI) predisposes patients to an increased risk into progressive chronic kidney disease (CKD), however effective treatments are still elusive. This study aimed to investigate the therapeutic efficacy of human adipose-derived MSCs (hAD-MSCs) in the prevention of AKI-CKD transition, and illuminate the role of Sox9, a vital transcription factor in the development of kidney, in this process. C57BL/6 mice were subjected to unilateral renal ischemia/reperfusion (I/R) with or without hAD-MSC treatment. We found that hAD-MSC treatment upregulated the expression of tubular Sox9, promoted tubular regeneration, attenuated AKI, and mitigated subsequent renal fibrosis. However, these beneficial effects were abolished by a drug inhibiting the release of exosomes from hAD-MSCs. Similarly, Sox9 inhibitors reversed these protective effects. Further, we verified that hAD-MSCs activated tubular Sox9 and prevented TGF-β1-induced transformation of TECs into pro-fibrotic phenotype through exosome shuttling in vitro, but the cells did not inhibit TGF-β1-induced transition of fibroblasts into myofibroblasts. Inhibiting the release of exosomes from hAD-MSCs or the expression of Sox9 in TECs reversed these antifibrotic effects. In conclusion, hAD-MSCs employed exosomes to mitigate AKI-CKD transition through tubular epithelial cell dependent activation of Sox9.
Macrophages play an important role in renal injury and repair after acute kidney injury (AKI) and the subsequent chronic kidney disease (CKD) that often results. However, as macrophages have a high degree of plasticity and heterogeneity, the function(s) of macrophage subtypes in AKI-to-CKD progression are not fully understood. Here, we focused on Ly6C − macrophages, which are derived from the embryonic yolk sac and post-development become resident in the kidneys. We found that C–C chemokine receptor type 2 (CCR2) deficiency, which blocks the migration of Ly6C + macrophages from the bone marrow to the sites of injury, alleviated ischemia-induced AKI in mice. Unexpectedly, though, CCR2 deficiency worsened the subsequent renal fibrosis, which was marked by notable intra-renal infiltration of Ly6C − macrophages. These Ly6C − macrophages were greater in number in both the acute and chronic phases after ischemia reperfusion (I/R) in kidneys of wild type (WT) mice, and we showed them to be derived from the bone marrow by bone marrow chimerism. Clodronate Liposomes (CLs)-mediated depletion of renal Ly6C − macrophages in CCR2 − /− mice or in WT mice after I/R alleviated the renal injury and fibrosis. On the contrary, adoptive transfer of Ly6C − macrophages from injured kidneys of WT mice into immune-deficient mice was sufficient to induce renal injury and fibrosis. Transcriptome sequencing of Ly6C − macrophages from injured kidneys revealed that they secreted various cytokines and growth factors, which were associated with the transdifferentiation of fibroblasts into myofibroblasts. This transdifferentiation effect was further supported by in vitro studies showing that Ly6C − macrophages induced the secretion of extracellular matrix proteins from co-cultured fibroblasts. In conclusion, the presence of bone marrow-derived Ly6C − macrophages after ischemia induces AKI and worsens subsequent CKD.
The purpose of this study was to describe radiologic anatomy of the left atrium diverticulum. There were 20 patients with 27 left atrium diverticulums in 120 consecutive patients who underwent CT of coronary angiography. The presence probability of left atrium diverticulum was 16.7%, male of it was 13.0%, female was 17.6%. There was no difference on gender (P > 0.05). There were four patients accompanying with variation of pulmonary vein at one time. The diverticulum might be single or multiple, cystiform or tubiform. It could locate anterior wall or posterior wall or superior wall of left atrium. Left atrium diverticulums which was single, cystiform, and located in anterior wall were common. The cervix width of diverticulum was 4.9 +/- 3.2 mm, the body height of them was 5.4 +/- 2.0 mm. The ratio of body height to cervix width was from 0.47 to 4.08 (median 1.16). Ten patients of them undertook cardiac ultrasound examination at same time. There were five patients who left atrial diastolic function decreased, four patients who left ventricular systolic function decreased. Three of them both existed left atrial diastolic function decreasing and left ventricular systolic function decreasing, accompanied with mitral or aortic regurgitation. No patient was found that left atrium pressure or left ventricle diastolic pressure was increasing. The left atrium diverticulums of ten patients were probably congenital because their hemodynamical status cannot lead to diverticulum formation. It can be proved by reexamination after therapy or autopsy at last. In conclusion, multi-detector row computed tomography could provide anatomy details of left atrium diverticulum to help to finish heart and chest surgery successfully.
Bromodomain PHD finger transcription factor (BPTF), a core subunit of nucleosome-remodeling factor (NURF) complex, plays an important role in chromatin remodeling. However, its precise function and molecular mechanism involved in hepatocellular carcinoma (HCC) growth are still poorly defined. Here, we demonstrated the tumor-promoting role of BPTF in HCC progression. BPTF was highly expressed in HCC cells and tumor tissues of HCC patients compared with normal liver cells and tissues. Knockdown of BPTF inhibited cell proliferation, colony formation and stem cell-like traits in HCC cells. In addition, BPTF knockdown effectively sensitized the anti-tumor effect of chemotherapeutic drugs and induced more apoptosis in HCC cells. Consistently, knockdown of BPTF in a xenograft mouse model also suppressed tumor growth and metastasis accompanied by the suppression of cancer stem cells (CSC)-related protein markers. Moreover, the mechanism study showed that the tumor-promoting role of BPTF in HCC was realized by transcriptionally regulating the expression of human telomerase reverse transcriptase (hTERT). Furthermore, we found that HCC patients with high BPTF expression displayed high hTERT expression, and high BPTF or hTERT expression level was positively correlated with advanced malignancy and poor prognosis in HCC patients. Collectively, our results demonstrate that BPTF promotes HCC growth by targeting hTERT and suggest that the BPTF-hTERT axis maybe a novel and potential therapeutic target in HCC.
The LAAd is an uncommon site of origin for focal AT (2.1% incidence). In this case series, focal ATs originating from the LAAd had typical electrophysiological and electrocardiographic characteristics. Focal ablation yielded high acute success rate with low rate of recurrence during follow-up.
Oxytocin (OXT) has been shown to suppress appetite, induce weight loss, and improve glycemic control and lipid metabolism in several species, including humans, monkeys, and rodents. However, OXT’s short half-life in circulation and lack of receptor selectivity limit its application and efficacy. In this study, we report an OXT peptide analog (OXTGly) that is potent and selective for the OXT receptor (OXTR). OXT, but not OXTGly, activated vasopressin receptors in vitro and acutely increased blood pressure in vivo when administered IP. OXT suppressed food intake in mice, whereas OXTGly had a moderate effect on food intake when administered IP or intracerebroventricularly. Both OXT (IP) and OXTGly (IP) improved glycemic control in glucose tolerance tests. Additionally, both OXT (IP) and OXTGly (IP) stimulated insulin, glucagon-like peptide 1, and glucagon secretion in mice. We generated lipid-conjugated OXT (acylated-OXT) and OXTGly (acylated-OXTGly) and demonstrated that these molecules have significantly extended half-lives in vivo. Compared with OXT, 2-week treatment of diet-induced obese mice with acylated-OXT [subcutaneous(ly) (SC)] resulted in enhanced body weight reduction, an improved lipid profile, and gene expression changes consistent with increased lipolysis and decreased gluconeogenesis. Treatment with acylated-OXTGly (SC) also resulted in a statistically significant weight loss, albeit to a lesser degree compared with acylated-OXT treatment. In conclusion, we demonstrate that selective activation of the OXTR pathway results in both acute and chronic metabolic benefits, whereas potential activation of vasopressin receptors by nonselective OXT analogs causes physiological stress that contributes to additional weight loss.
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