Evidence map›Paper›PMID 40570183›Full record

ArticleCardiovascular research2025

The role of uremic toxin indoxyl sulfate in the pathophysiology of aortic valve stenosis.

Philip Düsing, Isabel Göbel, Ansgar Ackerschott, Laurine Reese, Patrick Giavalisco, Frederik Dethloff, Sven Thomas Niepmann, Marta Stei, Thomas Beiert, Sebastian Zimmer and 4 more

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Article in Cardiovascular research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed.

  1. Review
  2. Article
  3. Review
  4. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

14 authors.

Philip DüsingDepartment of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II, Venusberg Campus 1, Bonn 53127, Germany.ORCID 0000-0003-1394-6471
Isabel GöbelDepartment of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II, Venusberg Campus 1, Bonn 53127, Germany.
Ansgar AckerschottDepartment of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II, Venusberg Campus 1, Bonn 53127, Germany.ORCID 0000-0001-6473-2399
Laurine ReeseDepartment of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II, Venusberg Campus 1, Bonn 53127, Germany.
Patrick GiavaliscoMax Planck Institute for Biology of Ageing, Metabolomics Core Facility, Cologne, Germany.
Frederik DethloffMax Planck Institute for Biology of Ageing, Metabolomics Core Facility, Cologne, Germany.
Sven Thomas NiepmannDepartment of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II, Venusberg Campus 1, Bonn 53127, Germany.
Marta SteiDepartment of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II, Venusberg Campus 1, Bonn 53127, Germany.
Thomas BeiertDepartment of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II, Venusberg Campus 1, Bonn 53127, Germany.
Sebastian ZimmerDepartment of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II, Venusberg Campus 1, Bonn 53127, Germany.ORCID 0000-0002-1531-2088
Christian KurtsInstitute of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn, Germany.
Georg NickenigDepartment of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II, Venusberg Campus 1, Bonn 53127, Germany.
Felix JansenKardiologie Köln, Gemeinschaftspraxis Kardiologie, Cologne, Germany.
Andreas ZietzerDepartment of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II, Venusberg Campus 1, Bonn 53127, Germany.ORCID 0000-0001-5759-7627

Funding

Corona-FoundationDeutsche Forschungsgemeinschaft 397484323-TRR 259Deutsche Forschungsgemeinschaft 514976099German Cardiac SocietyGerman Federal Ministry of Education and Research 01EO2107University of Bonn 2020-1A-06University of Bonn 2022-1A-05 to PD
6 · The paper itself

Abstract

aimsChronic kidney disease (CKD) is closely associated with cardiovascular disease (CVD). This includes aortic valve stenosis (AS), one of the most common valve diseases among adults. CKD leads to the retention of uremic toxins such as indoxyl sulfate (IS), which is known to induce inflammatory and pro-calcific processes. We hypothesize that IS specifically induces AS formation. METHODS AND

resultsStimulation of human valvular interstitial cells (VICs) with IS in addition to phosphate led to increased calcification. RNA sequencing identified naked cuticle homologue 2 (NKD2) as an up-regulated gene in VICs under uremic conditions. Knockdown of NKD2 reduced calcification of VICs and upregulation of IL-6. The organic anion transporting polypeptide 3A1 (OAT3A1) was identified to mediate IS uptake as well as upregulation of NKD2 and IL-6. We identified NF-κB signalling to be involved in IS-induced IL-6 upregulation. In vivo, we investigated combined models of adenine-induced kidney injury or oral IS supplementation with wire injury-induced AS in C57BL/6J mice. Echocardiography showed aggravated AS in uremic mice compared with control mice after wire injury. Explanted valves from uremic mice with AS exhibited a significant increase in macrophage infiltration, fibrotic areas and valvular NKD2 expression compared with controls. IS-treated mice showed aggravated AS compared with control mice. This was accompanied by more prominent valve fibrosis, macrophage infiltration, and NKD2 expression in explanted valves of IS-treated mice. In the blood and bone marrow, IS treatment led to the differentiation of monocytes into intermediate and non-classical monocytes. This was paralleled by IS-induced monocyte adhesion to valvular endothelial cells in vitro.

conclusionUremic conditions aggravate AS development in mice by inducing valvular fibrosis and macrophage infiltration. IS is involved in this process and stimulates monocyte differentiation and adhesion to the valvular endothelium. On a cellular level, we hypothesize that IS-mediated NKD2 induction leads to a calcifying and inflammatory response in VICs.

Indexed as

Aortic ValveAortic Valve StenosisCalcinosisIndicanRenal Insufficiency, ChronicUremiaUremic ToxinsAdenineAnimalsCells, CulturedDisease Models, AnimalFibrosisHumansInterleukin-6MacrophagesMaleAdenineIL6 protein, humanIndicanInterleukin-6interleukin-6, mouseNF-kappa BOrganic Anion TransportersUremic ToxinsAdenineAortic valve stenosisCalcificationCardiorenal syndromeChronic kidney diseaseFibrosisIndoxyl sulfateInflammationMouseNaked cuticle homologue 2Organic anion transporting polypeptide 3A1PhosphateUremiaUremic toxins

Identifiers

PMID40570183

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.