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Sirtuin 6 and renal injury: another link in the β-catenin chain?
Gewin LS
(2020) Kidney Int 97: 24-27
MeSH Terms: Fibrosis, Humans, Kidney, Kidney Diseases, Sirtuins, beta Catenin
Show Abstract · Added March 18, 2020
A protective role for sirtuin 6 (Sirt6) in the context of chronic renal injury is reported by Cai et al. in this issue of Kidney International. The mechanism is thought to be mediated by Sirt6's deacetylase activity, specifically on β-catenin target genes. This commentary discusses these results and the interaction between Sirt6 and β-catenin within the broader context of β-catenin signaling and injury.
Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
0 Communities
1 Members
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6 MeSH Terms
Proximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responses.
Kishi S, Brooks CR, Taguchi K, Ichimura T, Mori Y, Akinfolarin A, Gupta N, Galichon P, Elias BC, Suzuki T, Wang Q, Gewin L, Morizane R, Bonventre JV
(2019) J Clin Invest 129: 4797-4816
MeSH Terms: Animals, Ataxia Telangiectasia Mutated Proteins, DNA Damage, DNA Repair, Disease Models, Animal, Female, Fibrosis, Humans, Kidney Diseases, Kidney Tubules, Proximal, Male, Mice, Mice, Knockout, Organoids
Show Abstract · Added March 18, 2020
Maladaptive proximal tubule (PT) repair has been implicated in kidney fibrosis through induction of cell-cycle arrest at G2/M. We explored the relative importance of the PT DNA damage response (DDR) in kidney fibrosis by genetically inactivating ataxia telangiectasia and Rad3-related (ATR), which is a sensor and upstream initiator of the DDR. In human chronic kidney disease, ATR expression inversely correlates with DNA damage. ATR was upregulated in approximately 70% of Lotus tetragonolobus lectin-positive (LTL+) PT cells in cisplatin-exposed human kidney organoids. Inhibition of ATR resulted in greater PT cell injury in organoids and cultured PT cells. PT-specific Atr-knockout (ATRRPTC-/-) mice exhibited greater kidney function impairment, DNA damage, and fibrosis than did WT mice in response to kidney injury induced by either cisplatin, bilateral ischemia-reperfusion, or unilateral ureteral obstruction. ATRRPTC-/- mice had more cells in the G2/M phase after injury than did WT mice after similar treatments. In conclusion, PT ATR activation is a key component of the DDR, which confers a protective effect mitigating the maladaptive repair and consequent fibrosis that follow kidney injury.
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14 MeSH Terms
Inactivation of in Abcg2 lineage-derived cells drives the appearance of polycystic lesions and fibrosis in the adult kidney.
Gewin LS, Summers ME, Harral JW, Gaskill CF, Khodo SN, Neelisetty S, Sullivan TM, Hopp K, Reese JJ, Klemm DJ, Kon V, Ess KC, Shi W, Majka SM
(2019) Am J Physiol Renal Physiol 317: F1201-F1210
MeSH Terms: ATP Binding Cassette Transporter, Subfamily G, Member 2, Animals, Cell Lineage, Female, Fibrosis, Kidney Tubules, Proximal, Male, Mice, Myofibroblasts, Polycystic Kidney Diseases, Selective Estrogen Receptor Modulators, Tamoxifen, Tuberous Sclerosis Complex 2 Protein
Show Abstract · Added March 18, 2020
Tuberous sclerosis complex 2 (TSC2), or tuberin, is a pivotal regulator of the mechanistic target of rapamycin signaling pathway that controls cell survival, proliferation, growth, and migration. Loss of function manifests in organ-specific consequences, the mechanisms of which remain incompletely understood. Recent single cell analysis of the kidney has identified ATP-binding cassette G2 (Abcg2) expression in renal proximal tubules of adult mice as well as a in a novel cell population. The impact in adult kidney of knockdown in the Abcg2-expressing lineage has not been evaluated. We engineered an inducible system in which expression of truncated , lacking exons 36-37 with an intact 3' region and polycystin 1, is driven by Here, we demonstrate that selective expression of in the Abcg2 lineage drives recombination in proximal tubule epithelial and rare perivascular mesenchymal cells, which results in progressive proximal tubule injury, impaired kidney function, formation of cystic lesions, and fibrosis in adult mice. These data illustrate the critical importance of function in the Abcg2-expressing proximal tubule epithelium and mesenchyme during the development of cystic lesions and remodeling of kidney parenchyma.
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13 MeSH Terms
Fibroblast-specific plasminogen activator inhibitor-1 depletion ameliorates renal interstitial fibrosis after unilateral ureteral obstruction.
Yao L, Wright MF, Farmer BC, Peterson LS, Khan AM, Zhong J, Gewin L, Hao CM, Yang HC, Fogo AB
(2019) Nephrol Dial Transplant 34: 2042-2050
MeSH Terms: Actins, Animals, Collagen Type I, Connective Tissue Growth Factor, Extracellular Matrix Proteins, Fibroblasts, Fibrosis, Kidney Diseases, Mice, Mice, Knockout, Nerve Tissue Proteins, Serpin E2, Transforming Growth Factor beta, Ureteral Obstruction
Show Abstract · Added March 18, 2020
BACKGROUND - Plasminogen activator inhibitor-1 (PAI-1) expression increases extracellular matrix deposition and contributes to interstitial fibrosis in the kidney after injury. While PAI-1 is ubiquitously expressed in the kidney, we hypothesized that interstitial fibrosis is strongly dependent on fibroblast-specific PAI-1 (fbPAI-1).
METHODS - Tenascin C Cre (TNC Cre) and fbPAI-1 knockdown (KD) mice with green fluorescent protein (GFP) expressed within the TNC construct underwent unilateral ureteral obstruction and were sacrificed 10 days later.
RESULTS - GFP+ cells in fbPAI-1 KD mice showed significantly reduced PAI-1 expression. Interstitial fibrosis, measured by Sirius red staining and collagen I western blot, was significantly decreased in fbPAI-1 KD compared with TNC Cre mice. There was no significant difference in transforming growth factor β (TGF-β) expression or its activation between the two groups. However, GFP+ cells from fbPAI-1 KD mice had lower TGF β and connective tissue growth factor (CTGF) expression. The number of fibroblasts was decreased in fbPAI-1 KD compared with TNC Cre mice, correlating with decreased alpha smooth muscle actin (α-SMA) expression and less fibroblast cell proliferation. TNC Cre mice had decreased E-cadherin, a marker of differentiated tubular epithelium, in contrast to preserved expression in fbPAI-1 KD. F4/80-expressing cells, mostly CD11c+/F4/80+ cells, were increased while M1 macrophage markers were decreased in fbPAI-1 KD compared with TNC Cre mice.
CONCLUSION - These findings indicate that fbPAI-1 depletion ameliorates interstitial fibrosis by decreasing fibroblast proliferation in the renal interstitium, with resulting decreased collagen I. This is linked to decreased M1 macrophages and preserved tubular epithelium.
© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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14 MeSH Terms
Dual inhibition of endothelial miR-92a-3p and miR-489-3p reduces renal injury-associated atherosclerosis.
Wiese CB, Zhong J, Xu ZQ, Zhang Y, Ramirez Solano MA, Zhu W, Linton MF, Sheng Q, Kon V, Vickers KC
(2019) Atherosclerosis 282: 121-131
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Aorta, Atherosclerosis, Cell Line, Disease Models, Animal, Endothelium, Vascular, Female, Gene Expression Regulation, HEK293 Cells, Humans, Kidney Diseases, Mice, Mice, Knockout, ApoE, MicroRNAs, Nephrectomy, Nuclear Proteins, Phenotype, Phosphorylation, RNA, Small Interfering, STAT3 Transcription Factor, Signal Transduction, Transcriptome, Transforming Growth Factor beta
Show Abstract · Added April 10, 2019
BACKGROUND AND AIMS - Cardiovascular disease (CVD) is the leading cause of death in chronic kidney disease (CKD) patients, however, the underlying mechanisms that link CKD and CVD are not fully understood and limited treatment options exist in this high-risk population. microRNAs (miRNA) are critical regulators of gene expression for many biological processes in atherosclerosis, including endothelial dysfunction and inflammation. We hypothesized that renal injury-induced endothelial miRNAs promote atherosclerosis. Here, we demonstrate that dual inhibition of endothelial miRNAs inhibits atherosclerosis in the setting of renal injury.
METHODS - Aortic endothelial miRNAs were analyzed in apolipoprotein E-deficient (Apoe) mice with renal damage (5/6 nephrectomy, 5/6Nx) by real-time PCR. Endothelial miR-92a-3p and miR-489-3p were inhibited by locked-nucleic acid (LNA) miRNA inhibitors complexed to HDL.
RESULTS - Renal injury significantly increased endothelial miR-92a-3p levels in Apoe;5/6Nx mice. Dual inhibition of miR-92a-3p and miR-489-3p in Apoe;5/6Nx with a single injection of HDL + LNA inhibitors significantly reduced atherosclerotic lesion area by 28.6% compared to HDL + LNA scramble (LNA-Scr) controls. To examine the impact of dual LNA treatment on aortic endothelial gene expression, total RNA sequencing was completed, and multiple putative target genes and pathways were identified to be significantly altered, including the STAT3 immune response pathway. Among the differentially expressed genes, Tgfb2 and Fam220a were identified as putative targets of miR-489-3p and miR-92a-3p, respectively. Both Tgfb2 and Fam220a were significantly increased in aortic endothelium after miRNA inhibition in vivo compared to HDL + LNA-Scr controls. Furthermore, Tgfb2 and Fam220a were validated with gene reporter assays as direct targets of miR-489-3p and miR-92a-3p, respectively. In human coronary artery endothelial cells, over-expression and inhibition of miR-92a-3p decreased and increased FAM220A expression, respectively. Moreover, miR-92a-3p overexpression increased STAT3 phosphorylation, likely through direct regulation of FAM220A, a negative regulator of STAT3 phosphorylation.
CONCLUSIONS - These results support endothelial miRNAs as therapeutic targets and dual miRNA inhibition as viable strategy to reduce CKD-associated atherosclerosis.
Copyright © 2019. Published by Elsevier B.V.
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24 MeSH Terms
Pharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis.
Blackwood EA, Azizi K, Thuerauf DJ, Paxman RJ, Plate L, Kelly JW, Wiseman RL, Glembotski CC
(2019) Nat Commun 10: 187
MeSH Terms: Activating Transcription Factor 6, Animals, Animals, Newborn, Cells, Cultured, Cerebral Infarction, Disease Models, Animal, Endoplasmic Reticulum, Female, Heart Ventricles, Humans, Kidney, Kidney Diseases, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardial Infarction, Myocytes, Cardiac, Primary Cell Culture, Protective Agents, Proteostasis, Rats, Reperfusion Injury, Treatment Outcome, Unfolded Protein Response
Show Abstract · Added March 3, 2020
Pharmacologic activation of stress-responsive signaling pathways provides a promising approach for ameliorating imbalances in proteostasis associated with diverse diseases. However, this approach has not been employed in vivo. Here we show, using a mouse model of myocardial ischemia/reperfusion, that selective pharmacologic activation of the ATF6 arm of the unfolded protein response (UPR) during reperfusion, a typical clinical intervention point after myocardial infarction, transcriptionally reprograms proteostasis, ameliorates damage and preserves heart function. These effects were lost upon cardiac myocyte-specific Atf6 deletion in the heart, demonstrating the critical role played by ATF6 in mediating pharmacologically activated proteostasis-based protection of the heart. Pharmacological activation of ATF6 is also protective in renal and cerebral ischemia/reperfusion models, demonstrating its widespread utility. Thus, pharmacologic activation of ATF6 represents a proteostasis-based therapeutic strategy for ameliorating ischemia/reperfusion damage, underscoring its unique translational potential for treating a wide range of pathologies caused by imbalanced proteostasis.
0 Communities
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MeSH Terms
Next Generation Histology-Directed Imaging Mass Spectrometry Driven by Autofluorescence Microscopy.
Patterson NH, Tuck M, Lewis A, Kaushansky A, Norris JL, Van de Plas R, Caprioli RM
(2018) Anal Chem 90: 12404-12413
MeSH Terms: Animals, Female, Humans, Kidney Diseases, Malaria, Mice, Mice, Inbred BALB C, Microscopy, Fluorescence, Optical Imaging, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Show Abstract · Added October 15, 2019
Histology-directed imaging mass spectrometry (IMS) is a spatially targeted IMS acquisition method informed by expert annotation that provides rapid molecular characterization of select tissue structures. The expert annotations are usually determined on digital whole slide images of histological stains where the staining preparation is incompatible with optimal IMS preparation, necessitating serial sections: one for annotation, one for IMS. Registration is then used to align staining annotations onto the IMS tissue section. Herein, we report a next-generation histology-directed platform implementing IMS-compatible autofluorescence (AF) microscopy taken prior to any staining or IMS. The platform enables two histology-directed workflows, one that improves the registration process between two separate tissue sections using automated, computational monomodal AF-to-AF microscopy image registration, and a registration-free approach that utilizes AF directly to identify ROIs and acquire IMS on the same section. The registration approach is fully automated and delivers state of the art accuracy in histology-directed workflows for transfer of annotations (∼3-10 μm based on 4 organs from 2 species) while the direct AF approach is registration-free, allowing targeting of the finest structures visible by AF microscopy. We demonstrate the platform in biologically relevant case studies of liver stage malaria and human kidney disease with spatially targeted acquisition of sparsely distributed (composing less than one tenth of 1% of the tissue section area) malaria infected mouse hepatocytes and glomeruli in the human kidney case study.
0 Communities
2 Members
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MeSH Terms
Black Americans' Perspectives of Barriers and Facilitators of Community Screening for Kidney Disease.
Umeukeje EM, Wild MG, Maripuri S, Davidson T, Rutherford M, Abdel-Kader K, Lewis J, Wilkins CH, Cavanaugh K
(2018) Clin J Am Soc Nephrol 13: 551-559
MeSH Terms: Adult, Advertising, African Americans, Aged, Community Health Services, Cultural Competency, Emotions, Female, Focus Groups, Health Education, Health Knowledge, Attitudes, Practice, Health Services Accessibility, Humans, Kidney Diseases, Male, Middle Aged, Motivation, Religion, Trust, Young Adult
Show Abstract · Added November 29, 2018
BACKGROUND AND OBJECTIVES - Incidence of ESKD is three times higher in black Americans than in whites, and CKD prevalence continues to rise among black Americans. Community-based kidney disease screening may increase early identification and awareness of black Americans at risk, but it is challenging to implement. This study aimed to identify participants' perspectives of community kidney disease screening. The Health Belief Model provides a theoretic framework for conceptualization of these perspectives and optimization of community kidney disease screening activities.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - Researchers in collaboration with the Tennessee Kidney Foundation conducted three focus groups of adults in black American churches in Nashville, Tennessee. Questions examined views on CKD information, access to care, and priorities of kidney disease health. Content analysis was used. Guided by the Health Belief Model, themes were generated, and additional themes were derived from the data using an inductive approach.
RESULTS - Thirty-two black Americans completed the study in 2014. Participants were mostly women (79%) with a mean age of 56 years old (range, 24-78). Two major categories of barriers to kidney disease screening were identified: () participant factors, including limited kidney disease knowledge, spiritual/religious beliefs, emotions, and culture of the individual; and () logistic factors, including lack of convenience and incentives and poor advertisement. Potential facilitators of CKD screening included provision of CKD education, convenience of screening activities, and use of culturally sensitive and enhanced communication strategies. Program recommendations included partnering with trusted community members, selecting convenient locations, tailored advertising, and provision of compensation.
CONCLUSIONS - Findings of this study suggest that provider-delivered culturally sensitive education and stakeholder engagement are critical to increase trust, decrease fear, and maximize participation and early identification of kidney disease among black Americans considering community screening.
Copyright © 2018 by the American Society of Nephrology.
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20 MeSH Terms
Overcoming Translational Barriers in Acute Kidney Injury: A Report from an NIDDK Workshop.
Zuk A, Palevsky PM, Fried L, Harrell FE, Khan S, McKay DB, Devey L, Chawla L, de Caestecker M, Kaufman JS, Thompson BT, Agarwal A, Greene T, Okusa MD, Bonventre JV, Dember LM, Liu KD, Humphreys BD, Gossett D, Xie Y, Norton JM, Kimmel PL, Star RA
(2018) Clin J Am Soc Nephrol 13: 1113-1123
MeSH Terms: Acute Kidney Injury, Animals, Congresses as Topic, Disease Models, Animal, Humans, National Institute of Diabetes and Digestive and Kidney Diseases (U.S.), Translational Medical Research, United States
Show Abstract · Added October 23, 2018
AKI is a complex clinical condition associated with high mortality, morbidity, and health care costs. Despite improvements in methodology and design of clinical trials, and advances in understanding the underlying pathophysiology of rodent AKI, no pharmacologic agent exists for the prevention or treatment of AKI in humans. To address the barriers that affect successful clinical translation of drug targets identified and validated in preclinical animal models of AKI in this patient population, the National Institute of Diabetes and Digestive and Kidney Diseases convened the "AKI Outcomes: Overcoming Barriers in AKI" workshop on February 10-12, 2015. The workshop used a reverse translational medicine approach to identify steps necessary to achieve clinical success. During the workshop, breakout groups were charged first to design feasible, phase 2, proof-of-concept clinical trials for delayed transplant graft function, prevention of AKI (primary prevention), and treatment of AKI (secondary prevention and recovery). Breakout groups then were responsible for identification of preclinical animal models that would replicate the pathophysiology of the phase 2 proof-of-concept patient population, including primary and secondary end points. Breakout groups identified considerable gaps in knowledge regarding human AKI, our understanding of the pathophysiology of AKI in preclinical animal models, and the fidelity of cellular and molecular targets that have been evaluated preclinically to provide information regarding human AKI of various etiologies. The workshop concluded with attendees defining a new path forward to a better understanding of the etiology, pathology, and pathophysiology of human AKI.
Copyright © 2018 by the American Society of Nephrology.
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8 MeSH Terms
RAGE-aptamer attenuates deoxycorticosterone acetate/salt-induced renal injury in mice.
Taguchi K, Yamagishi SI, Yokoro M, Ito S, Kodama G, Kaida Y, Nakayama Y, Ando R, Yamada-Obara N, Asanuma K, Matsui T, Higashimoto Y, Brooks CR, Ueda S, Okuda S, Fukami K
(2018) Sci Rep 8: 2686
MeSH Terms: Acetates, Acute Kidney Injury, Aldosterone, Animals, Aptamers, Peptide, Blood Pressure, Desoxycorticosterone Acetate, Glycation End Products, Advanced, Hypertension, Kidney Diseases, Kidney Glomerulus, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptor for Advanced Glycation End Products, Receptors, Mineralocorticoid, Sodium Chloride, Dietary
Show Abstract · Added March 14, 2019
The mineralocorticoid receptor (MR) and its downstream signaling play an important role in hypertensive renal injury. The interaction of advanced glycation end products (AGE) with their receptor (RAGE) is involved in the progression of renal disease. However, the pathological crosstalk between AGE-RAGE axis and MR system in kidney derangement remains unclear. We screened DNA-aptamer directed against RAGE (RAGE-apt) in vitro and examined its effects on renal injury in uninephrectomized deoxycorticosterone acetate (DOCA)/salt-induced hypertensive mice. RAGE, GTP-bound Rac-1 (Rac1), and MR were co-localized in the podocytes of DOCA mice. The deletion of RAGE gene significantly inhibited mesangial matrix expansion and tubulointerstitial fibrosis in DOCA mice, which was associated with the reduction of glomerular oxidative stress, MR, Rac1, and urinary albumin excretion (UAE) levels. RAGE-apt attenuated the increase in carboxymethyllysine (CML), RAGE, nitrotyrosine, Rac1, and MR levels in the kidneys and reduced UAE in DOCA mice. Aldosterone (Aldo) increased nitrotyrosine, CML, and RAGE gene expression in murine podocytes, whereas CML stimulated MR and Rac1 levels, which were blocked by RAGE-apt. The present study indicates the crosstalk between the AGE-RAGE axis and Aldo-MR system, suggesting that RAGE-apt may be a novel therapeutic tool for the treatment of MR-associated renal diseases.
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18 MeSH Terms