Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact

Top read articles in the last 30 days

This list is updated daily and reflects the last month of access data. Articles older than two years will not be shown.

  • Research
KATP channels are necessary for glucose-dependent increases in amyloid-β and Alzheimer’s disease–related pathology
John Grizzanti, … , David M. Holtzman, Shannon L. Macauley
John Grizzanti, … , David M. Holtzman, Shannon L. Macauley
Published May 2, 2023
Citation Information: JCI Insight. 2023;8(10):e162454. https://doi.org/10.1172/jci.insight.162454.
View: Text | PDF
Research Article Aging Neuroscience

KATP channels are necessary for glucose-dependent increases in amyloid-β and Alzheimer’s disease–related pathology

  • Text
  • PDF
Abstract

Elevated blood glucose levels, or hyperglycemia, can increase brain excitability and amyloid-β (Aβ) release, offering a mechanistic link between type 2 diabetes and Alzheimer’s disease (AD). Since the cellular mechanisms governing this relationship are poorly understood, we explored whether ATP-sensitive potassium (KATP) channels, which couple changes in energy availability with cellular excitability, play a role in AD pathogenesis. First, we demonstrate that KATP channel subunits Kir6.2/KCNJ11 and SUR1/ABCC8 were expressed on excitatory and inhibitory neurons in the human brain, and cortical expression of KCNJ11 and ABCC8 changed with AD pathology in humans and mice. Next, we explored whether eliminating neuronal KATP channel activity uncoupled the relationship between metabolism, excitability, and Aβ pathology in a potentially novel mouse model of cerebral amyloidosis and neuronal KATP channel ablation (i.e., amyloid precursor protein [APP]/PS1 Kir6.2–/– mouse). Using both acute and chronic paradigms, we demonstrate that Kir6.2-KATP channels are metabolic sensors that regulate hyperglycemia-dependent increases in interstitial fluid levels of Aβ, amyloidogenic processing of APP, and amyloid plaque formation, which may be dependent on lactate release. These studies identify a potentially new role for Kir6.2-KATP channels in AD and suggest that pharmacological manipulation of Kir6.2-KATP channels holds therapeutic promise in reducing Aβ pathology in patients with diabetes or prediabetes.

Authors

John Grizzanti, William R. Moritz, Morgan C. Pait, Molly Stanley, Sarah D. Kaye, Caitlin M. Carroll, Nicholas J. Constantino, Lily J. Deitelzweig, James A. Snipes, Derek Kellar, Emily E. Caesar, Ryan J. Pettit-Mee, Stephen M. Day, Jonathon P. Sens, Noelle I. Nicol, Jasmeen Dhillon, Maria S. Remedi, Drew D. Kiraly, Celeste M. Karch, Colin G. Nichols, David M. Holtzman, Shannon L. Macauley

×

Total views: 2523


Aging alters mechanisms underlying voluntary movements in spinal motor neurons of mice, primates, and humans
Ryan W. Castro, … , Robert E. Settlage, Gregorio Valdez
Ryan W. Castro, … , Robert E. Settlage, Gregorio Valdez
Published May 8, 2023
Citation Information: JCI Insight. 2023;8(9):e168448. https://doi.org/10.1172/jci.insight.168448.
View: Text | PDF
Research Article Aging Neuroscience

Aging alters mechanisms underlying voluntary movements in spinal motor neurons of mice, primates, and humans

  • Text
  • PDF
Abstract

Spinal motor neurons have been implicated in the loss of motor function that occurs with advancing age. However, the cellular and molecular mechanisms that impair the function of these neurons during aging remain unknown. Here, we show that motor neurons do not die in old female and male mice, rhesus monkeys, and humans. Instead, these neurons selectively and progressively shed excitatory synaptic inputs throughout the soma and dendritic arbor during aging. Thus, aged motor neurons contain a motor circuitry with a reduced ratio of excitatory to inhibitory synapses that may be responsible for the diminished ability to activate motor neurons to commence movements. An examination of the motor neuron translatome (ribosomal transcripts) in male and female mice reveals genes and molecular pathways with roles in glia-mediated synaptic pruning, inflammation, axonal regeneration, and oxidative stress that are upregulated in aged motor neurons. Some of these genes and pathways are also found altered in motor neurons affected with amyotrophic lateral sclerosis (ALS) and responding to axotomy, demonstrating that aged motor neurons are under significant stress. Our findings show mechanisms altered in aged motor neurons that could serve as therapeutic targets to preserve motor function during aging.

Authors

Ryan W. Castro, Mikayla C. Lopes, Robert E. Settlage, Gregorio Valdez

×

Total views: 1499


Randomized crossover clinical trial of coenzyme Q10 and nicotinamide riboside in chronic kidney disease
Armin Ahmadi, … , Bryan R. Kestenbaum, Baback Roshanravan
Armin Ahmadi, … , Bryan R. Kestenbaum, Baback Roshanravan
Published May 9, 2023
Citation Information: JCI Insight. 2023. https://doi.org/10.1172/jci.insight.167274.
View: Text | PDF
Clinical Medicine In-Press Preview Clinical trials Nephrology

Randomized crossover clinical trial of coenzyme Q10 and nicotinamide riboside in chronic kidney disease

  • Text
  • PDF
Abstract

BACKGROUND. Current studies suggest mitochondrial dysfunction is a major contributor to impaired physical performance and exercise intolerance in chronic kidney disease (CKD). We conducted a clinical trial of coenzyme Q10 (CoQ10) and nicotinamide riboside (NR) to determine their impact on exercise tolerance and metabolic profile in CKD patients. METHODS. We conducted a randomized placebo-controlled, double blind, cross-over trial comparing CoQ10, NR, and placebo in 25 patients with eGFR of <60ml/min/1.73m2. Subjects received NR (1000 mg/day), CoQ10 (1200 mg/day), or placebo for 6 weeks each. Primary outcomes were aerobic capacity (VO2 peak) and work efficiency measured using graded cycle ergometry testing. We performed semi-targeted plasma metabolomics and lipidomics. RESUTS. Participant mean age was 61.0 ± 11.6 years and mean eGFR was 36.9±9.2 ml/min/1.73m2. Compared to placebo, we found no differences in VO2 peak (P=0.30, 0.17), total work (P=0.47, 0.77), and total work efficiency (P=0.46, 0.55) post NR or CoQ10 supplementation. NR decreased submaximal VO2 at 30W (P=0.03) and VO2 at 60W (P=0.07) compared to placebo. No changes in eGFR were observed post-NR or CoQ10 (P=0.14, 0.88). CoQ10 increased free fatty acids and decreased complex medium/long chain triglycerides. NR supplementation significantly altered TCA cycle intermediates and glutamate that are involved in reactions that exclusively use NAD+ and NADP+ as cofactors. NR decreased a broad range of lipid groups including triglycerides and ceramides. CONCLUSIONS. Six-weeks of treatment with NR or CoQ10 improved markers of systemic mitochondrial metabolism and lipid profiles but did not improve VO2 peak or total work efficiency. TRIAL REGISTRATION. ClinicalTrials.gov (NCT03579693) FUNDING. This study was supported by National Institutes of Diabetes and Digestive Kidney Diseases R01 DK101509 (to BK), R03 DK114502 (to BR), R01 DK125794 (to BR), R01 DK101509 (to JG), Dialysis Clinics Incorporated C-4112 (to BR), Northern California VA Health Care System (BR).

Authors

Armin Ahmadi, Gwenaelle Begue, Ana P. Valencia, Jennifer E. Norman, Benjamin Lidgard, Brian J. Bennett, Matthew P. Van Doren, David J. Marcinek, Sili Fan, David K. Prince, Jorge L. Gamboa, Jonathan Himmelfarb, Ian H. de Boer, Bryan R. Kestenbaum, Baback Roshanravan

×

Total views: 1209


TAp63, a methotrexate target in CD4+ T cells, suppresses Foxp3 expression and exacerbates autoimmune arthritis
Kensuke Suga, … , Osamu Ohara, Hiroshi Nakajima
Kensuke Suga, … , Osamu Ohara, Hiroshi Nakajima
Published May 22, 2023
Citation Information: JCI Insight. 2023;8(10):e164778. https://doi.org/10.1172/jci.insight.164778.
View: Text | PDF
Research Article Immunology

TAp63, a methotrexate target in CD4+ T cells, suppresses Foxp3 expression and exacerbates autoimmune arthritis

  • Text
  • PDF
Abstract

Methotrexate (MTX) is a standard, first-line therapy for rheumatoid arthritis (RA); however, its precise mechanisms of action other than antifolate activity are largely unknown. We performed DNA microarray analyses of CD4+ T cells in patients with RA before and after MTX treatment and found that TP63 was the most significantly downregulated gene after MTX treatment. TAp63, an isoform of TP63, was highly expressed in human IL-17–producing Th (Th17) cells and was suppressed by MTX in vitro. Murine TAp63 was expressed at high levels in Th cells and at lower levels in thymus-derived Treg cells. Importantly, TAp63 knockdown in murine Th17 cells ameliorated the adoptive transfer arthritis model. RNA-Seq analyses of human Th17 cells overexpressing TAp63 and those with TAp63 knockdown identified FOXP3 as a possible TAp63 target gene. TAp63 knockdown in CD4+ T cells cultured under Th17 conditions with low-dose IL-6 increased Foxp3 expression, suggesting that TAp63 balances Th17 cells and Treg cells. Mechanistically, TAp63 knockdown in murine induced Treg (iTreg) cells promoted hypomethylation of conserved noncoding sequence 2 (CNS2) of the Foxp3 gene and enhanced the suppressive function of iTreg cells. Reporter analyses revealed that TAp63 suppressed the activation of the Foxp3 CNS2 enhancer. Collectively, TAp63 suppresses Foxp3 expression and exacerbates autoimmune arthritis.

Authors

Kensuke Suga, Akira Suto, Shigeru Tanaka, Yutaka Sugawara, Takahiro Kageyama, Junichi Ishikawa, Yoshie Sanayama, Kei Ikeda, Shunsuke Furuta, Shin-Ichiro Kagami, Arifumi Iwata, Koichi Hirose, Kotaro Suzuki, Osamu Ohara, Hiroshi Nakajima

×

Total views: 1205


Longitudinal biomarkers and kidney disease progression after acute kidney injury
Yumeng Wen, … , Chirag R. Parikh, the ASSESS-AKI Consortium
Yumeng Wen, … , Chirag R. Parikh, the ASSESS-AKI Consortium
Published March 23, 2023
Citation Information: JCI Insight. 2023;8(9):e167731. https://doi.org/10.1172/jci.insight.167731.
View: Text | PDF
Clinical Medicine Nephrology

Longitudinal biomarkers and kidney disease progression after acute kidney injury

  • Text
  • PDF
Abstract

BACKGROUND Longitudinal investigations of murine acute kidney injury (AKI) suggest that injury and inflammation may persist long after the initial insult. However, the evolution of these processes and their prognostic values are unknown in patients with AKI.METHODS In a prospective cohort of 656 participants hospitalized with AKI, we measured 7 urine and 2 plasma biomarkers of kidney injury, inflammation, and tubular health at multiple time points from the diagnosis to 12 months after AKI. We used linear mixed-effect models to estimate biomarker changes over time, and we used Cox proportional hazard regressions to determine their associations with a composite outcome of chronic kidney disease (CKD) incidence and progression. We compared the gene expression kinetics of biomarkers in murine models of repair and atrophy after ischemic reperfusion injury (IRI).RESULTS After 4.3 years, 106 and 52 participants developed incident CKD and CKD progression, respectively. Each SD increase in the change of urine KIM-1, MCP-1, and plasma TNFR1 from baseline to 12 months was associated with 2- to 3-fold increased risk for CKD, while the increase in urine uromodulin was associated with 40% reduced risk for CKD. The trajectories of these biological processes were associated with progression to kidney atrophy in mice after IRI.CONCLUSION Sustained tissue injury and inflammation, and slower restoration of tubular health, are associated with higher risk of kidney disease progression. Further investigation into these ongoing biological processes may help researchers understand and prevent the AKI-to-CKD transition.FUNDING NIH and NIDDK (grants U01DK082223, U01DK082185, U01DK082192, U01DK082183, R01DK098233, R01DK101507, R01DK114014, K23DK100468, R03DK111881, K01DK120783, and R01DK093771).

Authors

Yumeng Wen, Leyuan Xu, Isabel Melchinger, Heather Thiessen-Philbrook, Dennis G. Moledina, Steven G. Coca, Chi-yuan Hsu, Alan S. Go, Kathleen D. Liu, Edward D. Siew, T. Alp Ikizler, Vernon M. Chinchilli, James S. Kaufman, Paul L. Kimmel, Jonathan Himmelfarb, Lloyd G. Cantley, Chirag R. Parikh, the ASSESS-AKI Consortium

×

Total views: 1173


CLUH functions as negative regulator of inflammation in human macrophages and determines ulcerative colitis pathogenesis
Shaziya Khan, … , Uday C. Ghoshal, Amit Lahiri
Shaziya Khan, … , Uday C. Ghoshal, Amit Lahiri
Published May 4, 2023
Citation Information: JCI Insight. 2023. https://doi.org/10.1172/jci.insight.161096.
View: Text | PDF
Research In-Press Preview Gastroenterology

CLUH functions as negative regulator of inflammation in human macrophages and determines ulcerative colitis pathogenesis

  • Text
  • PDF
Abstract

Altered mitochondrial function without a well-defined cause has been documented in the patients with ulcerative colitis (UC). In our efforts to understand UC pathogenesis, we observed reduced expression of clustered mitochondrial homologue, CLUH, only in the active UC tissues compared to the unaffected areas from the same patient and healthy controls. Stimulation with bacterial toll like receptor (TLR) ligands similarly reduced CLUH expression in the human primary macrophages. Further, CLUH negatively regulated secretion of pro-inflammatory cytokines IL6, TNF-α and rendered a pro-inflammatory niche in the TLR stimulated macrophage. CLUH was further found to bind to mitochondrial fission protein DRP-1 and also regulated DRP-1 transcription in the human macrophages. In the TLR ligand stimulated macrophages, absence of CLUH led to enhanced DRP-1 availability for mitochondrial fission and smaller dysfunctional mitochondrial pool was observed. Mechanistically, this fissioned mitochondrial pool in turn enhanced mitochondrial ROS production, reduced mitophagy and lysosomal function in the CLUH knockout macrophages. Remarkably, our studies in the mice model of colitis with CLUH knockdown displayed exacerbated disease pathology. Taken together, this is the first report signifying the role of CLUH in UC pathogenesis, by means of regulating inflammation via maintaining mitochondrial-lysosomal functions in the human macrophages and intestinal mucosa.

Authors

Shaziya Khan, Desh Raj, Shikha Sahu, Anam Naseer, Nishakumari C. Singh, Sunaina Kumari, Sharmeen Ishteyaque, Jyotsna Sharma, Promila Lakra, Madhav Nilakanth Mugale, Arun Kumar Trivedi, Mrigank Srivastava, Tulika Chandra, Vivek Bhosale, Manoj Kumar Barthwal, Shashi Kumar Gupta, Kalyan Mitra, Aamir Nazir, Uday C. Ghoshal, Amit Lahiri

×

Total views: 1118


Osteopontin promotes age-related adipose tissue remodeling through senescence-associated macrophage dysfunction
Daigo Sawaki, … , Gabor Czibik, Geneviève Derumeaux
Daigo Sawaki, … , Gabor Czibik, Geneviève Derumeaux
Published April 24, 2023
Citation Information: JCI Insight. 2023;8(8):e145811. https://doi.org/10.1172/jci.insight.145811.
View: Text | PDF
Research Article Aging Immunology

Osteopontin promotes age-related adipose tissue remodeling through senescence-associated macrophage dysfunction

  • Text
  • PDF
Abstract

Adipose tissue macrophages (ATMs) play an important role in obesity and inflammation, and they accumulate in adipose tissue (AT) with aging. Furthermore, increased ATM senescence has been shown in obesity-related AT remodeling and dysfunction. However, ATM senescence and its role are unclear in age-related AT dysfunction. Here, we show that ATMs (a) acquire a senescence-like phenotype during chronological aging; (b) display a global decline of basic macrophage functions such as efferocytosis, an essential process to preserve AT homeostasis by clearing dysfunctional or apoptotic cells; and (c) promote AT remodeling and dysfunction. Importantly, we uncover a major role for the age-associated accumulation of osteopontin (OPN) in these processes in visceral AT. Consistently, loss or pharmacologic inhibition of OPN and bone marrow transplantation of OPN–/– mice attenuate the ATM senescence-like phenotype, preserve efferocytosis, and finally restore healthy AT homeostasis in the context of aging. Collectively, our findings implicate pharmacologic OPN inhibition as a viable treatment modality to counter ATM senescence-mediated AT remodeling and dysfunction during aging.

Authors

Daigo Sawaki, Yanyan Zhang, Amel Mohamadi, Maria Pini, Zaineb Mezdari, Larissa Lipskaia, Suzain Naushad, Lucille Lamendour, Dogus Murat Altintas, Marielle Breau, Hao Liang, Maissa Halfaoui, Thaïs Delmont, Mathieu Surenaud, Déborah Rousseau, Takehiko Yoshimitsu, Fawzia Louache, Serge Adnot, Corneliu Henegar, Philippe Gual, Gabor Czibik, Geneviève Derumeaux

×

Total views: 1092


Hypothalamic and brainstem glucose-dependent insulinotropic polypeptide receptor neurons employ distinct mechanisms to affect feeding
Alice Adriaenssens, … , Fiona Gribble, Frank Reimann
Alice Adriaenssens, … , Fiona Gribble, Frank Reimann
Published May 22, 2023
Citation Information: JCI Insight. 2023;8(10):e164921. https://doi.org/10.1172/jci.insight.164921.
View: Text | PDF
Research Article Metabolism Neuroscience

Hypothalamic and brainstem glucose-dependent insulinotropic polypeptide receptor neurons employ distinct mechanisms to affect feeding

  • Text
  • PDF
Abstract

Central glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) signaling is critical in GIP-based therapeutics’ ability to lower body weight, but pathways leveraged by GIPR pharmacology in the brain remain incompletely understood. We explored the role of Gipr neurons in the hypothalamus and dorsal vagal complex (DVC) — brain regions critical to the control of energy balance. Hypothalamic Gipr expression was not necessary for the synergistic effect of GIPR/GLP-1R coagonism on body weight. While chemogenetic stimulation of both hypothalamic and DVC Gipr neurons suppressed food intake, activation of DVC Gipr neurons reduced ambulatory activity and induced conditioned taste avoidance, while there was no effect of a short-acting GIPR agonist (GIPRA). Within the DVC, Gipr neurons of the nucleus tractus solitarius (NTS), but not the area postrema (AP), projected to distal brain regions and were transcriptomically distinct. Peripherally dosed fluorescent GIPRAs revealed that access was restricted to circumventricular organs in the CNS. These data demonstrate that Gipr neurons in the hypothalamus, AP, and NTS differ in their connectivity, transcriptomic profile, peripheral accessibility, and appetite-controlling mechanisms. These results highlight the heterogeneity of the central GIPR signaling axis and suggest that studies into the effects of GIP pharmacology on feeding behavior should consider the interplay of multiple regulatory pathways.

Authors

Alice Adriaenssens, Johannes Broichhagen, Anne de Bray, Julia Ast, Annie Hasib, Ben Jones, Alejandra Tomas, Natalie Figueredo Burgos, Orla Woodward, Jo Lewis, Elisabeth O’Flaherty, Kimberley El, Canqi Cui, Norio Harada, Nobuya Inagaki, Jonathan Campbell, Daniel Brierley, David J. Hodson, Ricardo Samms, Fiona Gribble, Frank Reimann

×

Total views: 902


Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial
Mette Kruse Klausen, … , Tina Vilsbøll, Anders Fink-Jensen
Mette Kruse Klausen, … , Tina Vilsbøll, Anders Fink-Jensen
Published September 6, 2022
Citation Information: JCI Insight. 2022;7(19):e159863. https://doi.org/10.1172/jci.insight.159863.
View: Text | PDF
Clinical Medicine Clinical trials Neuroscience

Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial

  • Text
  • PDF
Abstract

Background Alcohol use disorder (AUD) is a chronic, relapsing brain disorder that accounts for 5% of deaths annually, and there is an urgent need to develop new targets for therapeutic intervention. The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduces alcohol consumption in rodents and nonhuman primates, but its efficacy in patients with AUD is unknown.Methods In a randomized, double-blinded, placebo-controlled clinical trial, treatment-seeking AUD patients were assigned to receive exenatide (2 mg subcutaneously) or placebo once weekly for 26 weeks, in addition to standard cognitive-behavioral therapy. The primary outcome was reduction in number of heavy drinking days. A subgroup also completed functional MRI (fMRI) and single-photon emission CT (SPECT) brain scans.Results A total of 127 patients were enrolled. Our data revealed that although exenatide did not significantly reduce the number of heavy drinking days compared with placebo, it significantly attenuated fMRI alcohol cue reactivity in the ventral striatum and septal area, which are crucial brain areas for drug reward and addiction. In addition, dopamine transporter availability was lower in the exenatide group compared with the placebo group. Exploratory analyses revealed that exenatide significantly reduced heavy drinking days and total alcohol intake in a subgroup of obese patients (BMI > 30 kg/m2). Adverse events were mainly gastrointestinal.Conclusion This randomized controlled trial on the effects of a GLP-1 receptor agonist in AUD patients provides new important knowledge on the effects of GLP-1 receptor agonists as a novel treatment target in addiction.Trial registration EudraCT: 2016-003343-11. ClinicalTrials.gov (NCT03232112).Funding Novavi Foundation; Research Foundation, Mental Health Services, Capital Region of Denmark; Research Foundation, Capital Region of Denmark; Ivan Nielsen Foundation; A.P. Moeller Foundation; Augustinus Foundation; Woerzner Foundation; Grosserer L.F. Foghts Foundation; Hartmann Foundation; Aase and Ejnar Danielsen Foundation; P.A. Messerschmidt and Wife Foundation; and Lundbeck Foundation.

Authors

Mette Kruse Klausen, Mathias Ebbesen Jensen, Marco Møller, Nina Le Dous, Anne-Marie Østergaard Jensen, Victoria Alberte Zeeman, Claas-Frederik Johannsen, Alycia Lee, Gerda Krog Thomsen, Julian Macoveanu, Patrick MacDonald Fisher, Matthew Paul Gillum, Niklas Rye Jørgensen, Marianne Lerbæk Bergmann, Henrik Enghusen Poulsen, Ulrik Becker, Jens Juul Holst, Helene Benveniste, Nora D. Volkow, Sabine Vollstädt-Klein, Kamilla Woznica Miskowiak, Claus Thorn Ekstrøm, Gitte Moos Knudsen, Tina Vilsbøll, Anders Fink-Jensen

×

Total views: 842


Cytokine storm–based mechanisms for extrapulmonary manifestations of SARS-CoV-2 infection
Maria Del Nogal Avila, … , Lionel C. Clement, Sumant S. Chugh
Maria Del Nogal Avila, … , Lionel C. Clement, Sumant S. Chugh
Published April 11, 2023
Citation Information: JCI Insight. 2023;8(10):e166012. https://doi.org/10.1172/jci.insight.166012.
View: Text | PDF
Research Article Nephrology

Cytokine storm–based mechanisms for extrapulmonary manifestations of SARS-CoV-2 infection

  • Text
  • PDF
Abstract

Viral illnesses like SARS-CoV-2 have pathologic effects on nonrespiratory organs in the absence of direct viral infection. We injected mice with cocktails of rodent equivalents of human cytokine storms resulting from SARS-CoV-2/COVID-19 or rhinovirus common cold infection. At low doses, COVID-19 cocktails induced glomerular injury and albuminuria in zinc fingers and homeoboxes 2 (Zhx2) hypomorph and Zhx2+/+ mice to mimic COVID-19–related proteinuria. Common Cold cocktail induced albuminuria selectively in Zhx2 hypomorph mice to model relapse of minimal change disease, which improved after depletion of TNF-α, soluble IL-4Rα, or IL-6. The Zhx2 hypomorph state increased cell membrane to nuclear migration of podocyte ZHX proteins in vivo (both cocktails) and lowered phosphorylated STAT6 activation (COVID-19 cocktail) in vitro. At higher doses, COVID-19 cocktails induced acute heart injury, myocarditis, pericarditis, acute liver injury, acute kidney injury, and high mortality in Zhx2+/+ mice, whereas Zhx2 hypomorph mice were relatively protected, due in part to early, asynchronous activation of STAT5 and STAT6 pathways in these organs. Dual depletion of cytokine combinations of TNF-α with IL-2, IL-13, or IL-4 in Zhx2+/+ mice reduced multiorgan injury and eliminated mortality. Using genome sequencing and CRISPR/Cas9, an insertion upstream of ZHX2 was identified as a cause of the human ZHX2 hypomorph state.

Authors

Maria Del Nogal Avila, Ranjan Das, Joubert Kharlyngdoh, Eduardo Molina-Jijon, Hector Donoro Blazquez, Stéphanie Gambut, Michael Crowley, David K. Crossman, Rasheed A. Gbadegesin, Sunveer S. Chugh, Sunjeet S. Chugh, Carmen Avila-Casado, Camille Macé, Lionel C. Clement, Sumant S. Chugh

×

Total views: 732

Show more results

Advertisement

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts