scholarly journals Renoprotective effect of Stat1 deletion in murine aristolochic acid nephropathy

2020 ◽  
Author(s):  
Wenguang Feng ◽  
Wei-Zhong Ying ◽  
Xingsheng Li ◽  
Lisa M. Curtis ◽  
Paul W. Sanders
Keyword(s):  
Aristolochic Acid ◽  
Interstitial Fibrosis ◽  
Kidney Injury ◽  
Proximal Tubules ◽  
Loss Of Function ◽  
Wild Type ◽  
Control Groups ◽  
Injury Score ◽  
Creatinine Concentration

Injured tubule epithelium stimulates a pro-fibrotic milieu that accelerates loss of function in chronic kidney disease (CKD). This study tested the role of STAT1 in the progressive loss of kidney function in aristolochic acid (AA) nephropathy, a model of CKD. Mean serum creatinine concentration increased in wild type (WT) littermates treated with AA, while Stat1-/- mice were protected. Focal increases in the apical expression of Kidney Injury Molecule (KIM)-1 were observed in the proximal tubules of WT mice with AA treatment, but was absent in Stat1-/- mice in the treatment group as well as in both control groups. A Composite Injury Score, an indicator of proximal tubule injury, was reduced in Stat1-/- mice treated with AA. Expression of integrin β6 and p-Smad2/3 in proximal tubules and interstitial collagen and fibronectin were observed in WT mice following AA treatment, but were all decreased in AA-treated Stat1-/- mice. The data indicated that STAT1 activation facilitated the development of progressive kidney injury and interstitial fibrosis in AA nephropathy.

scholarly journals The Constitutive Centromere Component CENP-50 Is Required for Recovery from Spindle Damage

2005 ◽  
Vol 25 (23) ◽  
pp. 10315-10328 ◽  
Author(s):  
Yukinori Minoshima ◽  
Tetsuya Hori ◽  
Masahiro Okada ◽  
Hiroshi Kimura ◽  
Tokuko Haraguchi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Rate ◽  
Mitotic Checkpoint ◽  
Loss Of Function ◽  
Wild Type ◽  
Centromere Function ◽  
Dt40 Cells ◽  
Precise Role ◽  
Chicken Dt40 Cell

ABSTRACT We identified CENP-50 as a novel kinetochore component. We found that CENP-50 is a constitutive component of the centromere that colocalizes with CENP-A and CENP-H throughout the cell cycle in vertebrate cells. To determine the precise role of CENP-50, we examined its role in centromere function by generating a loss-of-function mutant in the chicken DT40 cell line. The CENP-50 knockout was not lethal; however, the growth rate of cells with this mutation was slower than that of wild-type cells. We observed that the time for CENP-50-deficient cells to complete mitosis was longer than that for wild-type cells. Centromeric localization of CENP-50 was abolished in both CENP-H- and CENP-I-deficient cells. Coimmunoprecipitation experiments revealed that CENP-50 interacted with the CENP-H/CENP-I complex in chicken DT40 cells. We also observed severe mitotic defects in CENP-50-deficient cells with apparent premature sister chromatid separation when the mitotic checkpoint was activated, indicating that CENP-50 is required for recovery from spindle damage.

scholarly journals Proximal tubule-specific overexpression of netrin-1 suppresses acute kidney injury-induced interstitial fibrosis and glomerulosclerosis through suppression of IL-6/STAT3 signaling

2013 ◽  
Vol 304 (8) ◽  
pp. F1054-F1065 ◽  
Author(s):  
Punithavathi Ranganathan ◽  
Calpurnia Jayakumar ◽  
Ganesan Ramesh
Keyword(s):  
Acute Kidney Injury ◽  
Epithelial Cells ◽  
Interstitial Fibrosis ◽  
Kidney Injury ◽  
Transgenic Animals ◽  
Acute Injury ◽  
Tubular Epithelial Cells ◽  
Wild Type ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular

Acute kidney injury-induced organ fibrosis is recognized as a major risk factor for the development of chronic kidney disease, which remains one of the leading causes of death in the developed world. However, knowledge on molecules that may suppress the fibrogenic response after injury is lacking. In ischemic models of acute kidney injury, we demonstrate a new function of netrin-1 in regulating interstitial fibrosis. Acute injury was promptly followed by a rise in serum creatinine in both wild-type and netrin-1 transgenic animals. However, the wild-type showed a slow recovery of kidney function compared with netrin-1 transgenic animals and reached baseline by 3 wk. Histological examination showed increased infiltration of interstitial macrophages, extensive fibrosis, reduction of capillary density, and glomerulosclerosis. Collagen IV and α-smooth muscle actin expression was absent in sham-operated kidneys; however, their expression was significantly increased at 2 wk and peaked at 3 wk after reperfusion. These changes were reduced in the transgenic mouse kidney, which overexpresses netrin-1 in proximal tubular epithelial cells. Fibrosis was associated with increased expression of IL-6 and extensive and chronic activation of STAT3. Administration of IL-6 exacerbated fibrosis in vivo in wild-type, but not in netrin-1 transgenic mice kidney and increased collagen I expression and STAT3 activation in vitro in renal epithelial cells subjected to hypoxia-reoxygenation, which was suppressed by netrin-1. Our data suggest that proximal tubular epithelial cells may play a prominent role in interstitial fibrosis and that netrin-1 could be a useful therapeutic agent for treating kidney fibrosis.

scholarly journals Renalase and Biomarkers of Contrast-Induced Acute Kidney Injury

2015 ◽  
Vol 6 (1) ◽  
pp. 25-36 ◽  
Author(s):  
Maciej T. Wybraniec ◽  
Katarzyna Mizia-Stec
Keyword(s):  
Acute Kidney Injury ◽  
Renal Injury ◽  
Amine Oxidase ◽  
Kidney Injury ◽  
Cardiorenal Syndrome ◽  
Creatinine Concentration ◽  
Invasive Cardiology ◽  
Proximal Tubular ◽  
Novel Biomarkers

Background: Contrast-induced acute kidney injury (CI-AKI) remains one of the crucial issues related to the development of invasive cardiology. The massive use of contrast media exposes patients to a great risk of contrast-induced nephropathy and chronic kidney disease development, and increases morbidity and mortality rates. The serum creatinine concentration does not allow for a timely and accurate CI-AKI diagnosis; hence numerous other biomarkers of renal injury have been proposed. Renalase, a novel catecholamine-metabolizing amine oxidase, is synthesized mainly in proximal tubular cells and secreted into urine and blood. It is primarily engaged in the degradation of circulating catecholamines. Notwithstanding its key role in blood pressure regulation, renalase remains a potential CI-AKI biomarker, which was shown to be markedly downregulated in the aftermath of renal injury. In this sense, renalase appears to be the first CI-AKI marker revealing an actual loss of renal function and indicating disease severity. Summary: The purpose of this review is to summarize the contemporary knowledge about the application of novel biomarkers of CI-AKI and to highlight the potential role of renalase as a functional marker of contrast-induced renal injury. Key Messages: Renalase may constitute a missing biochemical link in the mutual interplay between kidney and cardiac pathology known as the cardiorenal syndrome.

scholarly journals Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis

2020 ◽  
Author(s):  
Benjamin Ng ◽  
Anissa A. Widjaja ◽  
Sivakumar Viswanathan ◽  
Jinrui Dong ◽  
Sonia P. Chothani ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Lung Fibroblasts ◽  
Loss Of Function ◽  
Wild Type ◽  
Reduced Body ◽  
Body Weights ◽  
Show Evidence ◽  
Similarities And Differences ◽  
The Impact

AbstractGenetic loss of function (LOF) in IL11RA infers IL11 signaling as important for fertility, fibrosis, inflammation and craniosynostosis. The impact of genetic LOF in IL11 has not been characterized. We generated IL11-knockout (Il11-/-) mice, which are born in normal Mendelian ratios, have normal hematological profiles and are protected from bleomycin-induced lung fibro-inflammation. Noticeably, baseline IL6 levels in the lungs of Il11-/- mice are lower than those of wild-type mice and are not induced by bleomycin damage, placing IL11 upstream of IL6. Lung fibroblasts from Il11-/- mice are resistant to pro-fibrotic stimulation and show evidence of reduced autocrine IL11 activity. Il11-/- female mice are infertile. Unlike Il11ra1-/- mice, Il11-/- mice do not have a craniosynostosis-like phenotype and exhibit mildly reduced body weights. These data highlight similarities and differences between LOF in IL11 or IL11RA while establishing further the role of IL11 signaling in fibrosis and stromal inflammation.

scholarly journals Dicer deficiency in proximal tubules exacerbates renal injury and tubulointerstitial fibrosis and upregulates Smad2/3

2018 ◽  
Vol 315 (6) ◽  
pp. F1822-F1832 ◽  
Author(s):  
Zhengwei Ma ◽  
Qingqing Wei ◽  
Ming Zhang ◽  
Jian-Kang Chen ◽  
Zheng Dong
Keyword(s):  
Kidney Disease ◽  
Renal Injury ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Proximal Tubules ◽  
Tubulointerstitial Fibrosis ◽  
Obstructive Nephropathy ◽  
Pathological Feature ◽  
Tubular Injury

Renal fibrosis is a common pathological feature in chronic kidney disease (CKD), including diabetic kidney disease (DKD) and obstructive nephropathy. Multiple microRNAs have been implicated in the pathogenesis of both DKD and obstructive nephropathy, although the overall role of microRNAs in tubular injury and renal fibrosis in CKD is unclear. Dicer (a key RNase III enzyme for microRNA biogenesis) was specifically ablated from kidney proximal tubules in mice via the Cre-lox system to deplete micoRNAs. Proximal tubular Dicer knockout (PT- Dicer KO) mice and wild-type (WT) littermates were subjected to streptozotocin (STZ) treatment to induce DKD or unilateral ureteral obstruction (UUO) to induce obstructive nephropathy. Renal hypertrophy, renal tubular apoptosis, kidney inflammation, and tubulointerstitial fibrosis were examined. Compared with WT mice, PT- Dicer KO mice showed more severe tubular injury and renal inflammation following STZ treatment. These mice also developed higher levels of tubolointerstitial fibrosis. Meanwhile, PT- Dicer KO mice had a significantly higher Smad2/3 expression in kidneys than WT mice (at 6 mo of age) in both control and STZ-treated mice. Similarly, UUO induced more severe renal injury, inflammation, and interstitial fibrosis in PT- Dicer KO mice than WT. Although we did not detect obvious Smad2/3 expression in sham-operated mice (2–3 mo old), significantly more Smad2/3 was induced in obstructed PT- Dicer KO kidneys. These results supported a protective role of Dicer-dependent microRNA synthesis in renal injury and fibrosis development in CKD, specifically in DKD and obstructive nephropathy. Depletion of Dicer and microRNAs may upregulate Smad2/3-related signaling pathway to enhance the progression of CKD.

Abstract 361: Creg1 Interacts With Sec8 to Promote Cell-cell Adhesion During Cardiomyogenesis

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Jie Liu ◽  
Yanmei Qi ◽  
Shu-Chan Hsu ◽  
Siavash Saadat ◽  
Saum Rahimi ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Es Cells ◽  
Embryonic Stem ◽  
Intercellular Junctions ◽  
Amino Acid Residues ◽  
Loss Of Function ◽  
Wild Type ◽  
Adhesion Sites ◽  
Cell Cell

Cellular repressor of E1A-stimulated genes 1 (CREG1) is a 24 kD glycoprotein essential for early embryonic development. Our immunofluorescence studies revealed that CREG1 is highly expressed at myocyte junctions in both embryonic and adult hearts. To explore it role in cardiomyogenesis, we employed gain- and loss-of-function analyses demonstrating that CREG1 is required for the differentiation of mouse embryonic stem (ES) cell into cohesive myocardium-like structures. Chimeric cultures of wild-type and CREG1 knockout ES cells expressing cardiac-specific reporters showed that the cardiomyogenic effect of CREG1 is cell autonomous. Furthermore, we identified a novel interaction between CREG1 and Sec8 of the exocyst complex, which tethers vesicles to the plasma membrane. Mutations of the amino acid residues D141 and P142 to alanine in CREG1 abolished its binding to Sec8. To address the role of the CREG1-Sec8 interaction in cardiomyogenesis, we rescued CREG1 knockout ES cells with wild-type and Sec8-binding mutant CREG1 and showed that CREG1 binding to Sec8 promotes cardiomyocyte differentiation and cohesion. Mechanistically, CREG1, Sec8 and N-cadherin all localize at cell-cell adhesion sites. CREG1 overexpression enhances the assembly of adherens and gap junctions. By contrast, its knockout inhibits the Sec8-N-cadherin interaction and induces their degradation. Finally, shRNA-mediated knockdown of Sec8 leads to cardiomyogenic defects similar to CREG1 knockout. These results suggest that the CREG1 binding to Sec8 enhances the assembly of intercellular junctions and promotes cardiomyogenesis.

scholarly journals MtBZR1 Plays an Important Role in Nodule Development in Medicago truncatula

2019 ◽  
Vol 20 (12) ◽  
pp. 2941
Author(s):  
Can Cui ◽  
Hongfeng Wang ◽  
Limei Hong ◽  
Yiteng Xu ◽  
Yang Zhao ◽  
...  
Keyword(s):  
Medicago Truncatula ◽  
Sinorhizobium Meliloti ◽  
Normal Growth ◽  
Dry Mass ◽  
Growth Conditions ◽  
Nodule Development ◽  
Functional Study ◽  
Loss Of Function ◽  
Wild Type

Brassinosteroid (BR) is an essential hormone in plant growth and development. The BR signaling pathway was extensively studied, in which BRASSINAZOLE RESISTANT 1 (BZR1) functions as a key regulator. Here, we carried out a functional study of the homolog of BZR1 in Medicago truncatula R108, whose expression was induced in nodules upon Sinorhizobium meliloti 1021 inoculation. We identified a loss-of-function mutant mtbzr1-1 and generated 35S:MtBZR1 transgenic lines for further analysis at the genetic level. Both the mutant and the overexpression lines of MtBZR1 showed no obvious phenotypic changes under normal growth conditions. After S. meliloti 1021 inoculation, however, the shoot and root dry mass was reduced in mtbzr1-1 compared with the wild type, caused by partially impaired nodule development. The transcriptomic analysis identified 1319 differentially expressed genes in mtbzr1-1 compared with wild type, many of which are involved in nodule development and secondary metabolite biosynthesis. Our results demonstrate the role of MtBZR1 in nodule development in M. truncatula, shedding light on the potential role of BR in legume–rhizobium symbiosis.

scholarly journals Potential role of imaging for assessing acute pancreatitis-induced acute kidney injury

2020 ◽  
pp. 20200802
Author(s):  
Yi Wang ◽  
Kaixiang Liu ◽  
Xisheng Xie ◽  
Bin Song
Keyword(s):  
Acute Kidney Injury ◽  
Acute Pancreatitis ◽  
Early Stage ◽  
Kidney Injury ◽  
Current Evidence ◽  
Advanced Imaging ◽  
Creatinine Concentration ◽  
New Techniques ◽  
Magnetic Resonance Imaging Mri

Acute kidney injury (AKI) is a common complication of acute pancreatitis (AP) that is associated with increased mortality. Conventional assessment of AKI is based on changes in serum creatinine concentration and urinary output. However, these examinations have limited accuracy and sensitivity for the diagnosis of early-stage AKI. This review summarizes current evidence on the use of advanced imaging approaches and artificial intelligence (AI) for the early prediction and diagnosis of AKI in patients with AP. CT scores, CT post-processing technology, Doppler ultrasound, and AI technology provide increasingly valuable information for the diagnosis of AP-induced AKI. Magnetic resonance imaging (MRI) also has potential for the evaluation of AP-induced AKI. For the accurate diagnosis of early-stage AP-induced AKI, more studies are needed that use these new techniques and that use AI in combination with advanced imaging technologies.

scholarly journals Disruption of CXCR6 Ameliorates Kidney Inflammation and Fibrosis in Deoxycorticosterone Acetate/Salt Hypertension

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuanbo Wu ◽  
Changlong An ◽  
Xiaogao Jin ◽  
Zhaoyong Hu ◽  
Yanlin Wang
Keyword(s):  
Knockout Mice ◽  
Critical Role ◽  
Kidney Injury ◽  
Wild Type ◽  
Salt Treatment ◽  
Hypertensive Nephropathy ◽  
Deoxycorticosterone Acetate ◽  
Kidney Fibrosis ◽  
Salt Hypertension

AbstractCirculating cells have a pathogenic role in the development of hypertensive nephropathy. However, how these cells infiltrate into the kidney are not fully elucidated. In this study, we investigated the role of CXCR6 in deoxycorticosterone acetate (DOCA)/salt-induced inflammation and fibrosis of the kidney. Following uninephrectomy, wild-type and CXCR6 knockout mice were treated with DOCA/salt for 3 weeks. Blood pressure was similar between wild-type and CXCR6 knockout mice at baseline and after treatment with DOCA/salt. Wild-type mice develop significant kidney injury, proteinuria, and kidney fibrosis after three weeks of DOCA/salt treatment. CXCR6 deficiency ameliorated kidney injury, proteinuria, and kidney fibrosis following treatment with DOCA/salt. Moreover, CXCR6 deficiency inhibited accumulation of bone marrow–derived fibroblasts and myofibroblasts in the kidney following treatment with DOCA/salt. Furthermore, CXCR6 deficiency markedly reduced the number of macrophages and T cells in the kidney after DOCA/salt treatment. In summary, our results identify a critical role of CXCR6 in the development of inflammation and fibrosis of the kidney in salt-sensitive hypertension.

scholarly journals Only Hyperuricemia with Crystalluria, but not Asymptomatic Hyperuricemia, Drives Progression of Chronic Kidney Disease

2020 ◽  
Vol 31 (12) ◽  
pp. 2773-2792
Author(s):  
Markus Sellmayr ◽  
Moritz Roman Hernandez Petzsche ◽  
Qiuyue Ma ◽  
Nils Krüger ◽  
Helen Liapis ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Aristolochic Acid ◽  
Interstitial Fibrosis ◽  
Ckd Progression ◽  
Fticr Mass Spectrometry ◽  
Progressive Decline ◽  
Granulomatous Interstitial Nephritis ◽  
Crystal Nephropathy ◽  
Aristolochic Acid I

BackgroundThe roles of asymptomatic hyperuricemia or uric acid (UA) crystals in CKD progression are unknown. Hypotheses to explain links between UA deposition and progression of CKD include that (1) asymptomatic hyperuricemia does not promote CKD progression unless UA crystallizes in the kidney; (2) UA crystal granulomas may form due to pre-existing CKD; and (3) proinflammatory granuloma-related M1-like macrophages may drive UA crystal-induced CKD progression.MethodsMALDI-FTICR mass spectrometry, immunohistochemistry, 3D confocal microscopy, and flow cytometry were used to characterize a novel mouse model of hyperuricemia and chronic UA crystal nephropathy with granulomatous nephritis. Interventional studies probed the role of crystal-induced inflammation and macrophages in the pathology of progressive CKD.ResultsAsymptomatic hyperuricemia alone did not cause CKD or drive the progression of aristolochic acid I-induced CKD. Only hyperuricemia with UA crystalluria due to urinary acidification caused tubular obstruction, inflammation, and interstitial fibrosis. UA crystal granulomas surrounded by proinflammatory M1-like macrophages developed late in this process of chronic UA crystal nephropathy and contributed to the progression of pre-existing CKD. Suppressing M1-like macrophages with adenosine attenuated granulomatous nephritis and the progressive decline in GFR. In contrast, inhibiting the JAK/STAT inflammatory pathway with tofacitinib was not renoprotective.ConclusionsAsymptomatic hyperuricemia does not affect CKD progression unless UA crystallizes in the kidney. UA crystal granulomas develop late in chronic UA crystal nephropathy and contribute to CKD progression because UA crystals trigger M1-like macrophage-related interstitial inflammation and fibrosis. Targeting proinflammatory macrophages, but not JAK/STAT signaling, can attenuate granulomatous interstitial nephritis.

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