Indoxyl Sulfate Induces Epithelial-to-Mesenchymal Transition in Rat Kidneys and Human Proximal Tubular Cells

Bolati, Dilinaer; Shimizu, Hidehisa; Higashiyama, Yukihiro; Nishijima, Fuyuhiko; Niwa, Toshimitsu

doi:10.1159/000330852

Cited by 67 publications

(67 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The following cell and organ systems were investigated (n of each study is in parentheses) ( Table 2): renal tubules (9), 34,[36][37][38][39]43,45,47,50 endothelium (6), [26][27][28][29][30]33 leukocytes (2), 30,31 whole vessels (2), 40,41 whole kidney (2), 40,42 cardiac cells (2), 35,49 smooth muscle cells (2), 46,51 hepatocytes (2), 32,51 intestinal cells (1), 48 and adipocytes (1). 44 A few studies concentrated on more than one target system: one study was on both the whole vessel and kidney 40 and one study was on leukocyte-endothelial interaction.…”

Section: Resultsmentioning

confidence: 99%

“…44 A few studies concentrated on more than one target system: one study was on both the whole vessel and kidney 40 and one study was on leukocyte-endothelial interaction. 30 Twenty-four studies concentrated on indoxyl sulfate, [26][27][28][29][30][32][33][34][35][36][37][38][39][40][41][42][43][46][47][48][49][50][51][52] and six studies concentrated on p-cresyl sulfate. 31,34,36,39,44,45 Three studies evaluated both compounds.…”

Section: Resultsmentioning

confidence: 99%

“…Of 14 animal studies, 10 studies were in rats, 37,38,[40][41][42][43]45,47,49,50 and four studies were in mice. 30,36,39,44 Several of the rat studies were in the specific Dahl salt-sensitive hypertensive rat strain, 37,38,[40][41][42][43]47,49,50 although in some of these studies, an effect in the wild type was also observed.…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate

Vanholder

Schepers

Pletinck

et al. 2014

Journal of the American Society of Nephrology

562

463

View full text Add to dashboard Cite

A growing number of publications supports a biologic effect of the protein-bound uremic retention solutes indoxyl sulfate and p-cresyl sulfate. However, the use of unrealistically high free concentrations of these compounds and/or inappropriately low albumin concentrations may blur the interpretation of these results. Here, we performed a systematic review, selecting only studies in which, depending on the albumin concentration, real or extrapolated free concentrations of indoxyl sulfate and p-cresyl sulfate remained in the uremic range. The 27 studies retrieved comprised in vitro and animal studies. A quality score was developed, giving 1 point for each of the following criteria: six or more experiments, confirmation by more than one experimental approach, neutralization of the biologic effect by counteractive reagents or antibodies, use of a real-life model, and use of dose-response analyses in vitro and/or animal studies. The overall average score was 3 of 5 points, with five studies scoring 5 of 5 points and six studies scoring 4 of 5 points, highlighting the superior quality of a substantial number of the retrieved studies. In the 11 highest scoring studies, most functional deteriorations were related to uremic cardiovascular disease and kidney damage. We conclude that our systematic approach allowed the retrieval of methodologically correct studies unbiased by erroneous conditions related to albumin binding. Our data seem to confirm the toxicity of indoxyl sulfate and p-cresyl sulfate and support their roles in vascular and renal disease progression.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate

Vanholder

Schepers

Pletinck

et al. 2014

Journal of the American Society of Nephrology

562

463

View full text Add to dashboard Cite

show abstract

“…It has been shown that IS has a strong pro-oxidative activity by inducing reactive oxygen species (ROS) production. Recent studies, including our own, revealed that IS-induced oxidative stress cannot only damage renal cells and aggravate the progression of CKD, [16][17][18] but also has harmful effects on other tissues, such as inducing vascular endothelial damage and myocardial hypertrophy. 19,20 In addition, serum IS associates with dialysis graft thrombosis after endovascular interventions.…”

Section: Introductionmentioning

confidence: 85%

Indoxyl sulfate induces platelet hyperactivity and contributes to chronic kidney disease–associated thrombosis in mice

Yang

Du²,

Wang³

et al. 2017

Blood

122

119

View full text Add to dashboard Cite

Key Points• Uremic solute IS increases platelet activity via activation of ROS/p38MAPK signaling.• Klotho counteracts ISinduced thrombosis by restraining platelet hyperactivity.Thrombosis is a common complication of chronic kidney disease (CKD), but the causes and mechanisms of CKD-associated thrombosis are not well clarified. Here, we show that platelet activity is remarkably enhanced in CKD mice, with increase of serum indoxyl sulfate (IS), a typical uremic toxin, which cannot be effectively cleared by routine dialysis. Ex vivo and in vitro experiments reveal that IS displays a distinct ability to enhance platelet activities, including elevated response to collagen and thrombin, increases in plateletderived microparticles, and platelet-monocyte aggregates. The flow chamber assay and carotid artery thrombosis model demonstrate that IS-induced platelet hyperactivity contributes to thrombus formation. Further investigations disclose that reactive oxygen species (ROS)-mediated p38MAPK signaling plays a key role in IS-induced platelet hyperactivity. Moreover, we show that Klotho, which is expressed dominantly in the kidneys, has the capacity to counteract IS-induced platelet hyperactivity by inhibiting ROS/p38MAPK signaling, whereas Klotho reduction may aggravate the effect of IS on platelet activation in CKD and klotho 1/2 mice. Finally, we demonstrate that Klotho protein treatment can protect against IS-induced thrombosis and atherosclerosis in apoE 2/2 mice. Our findings uncover the mechanism of platelet hyperactivity induced by IS and provide new insights into the pathogenesis and treatment of CKD-associated thrombosis.

show abstract

“…The secreted TGF-β1 stimulates the production of TIMP-1 and collagen. The damaged tubular cells are transformed into myofibroblasts through an epithelial-to-mesenchymal transition (14), these changes facilitate interstitial fibrosis. Thus, indoxyl sulfate accumulated in uremic serum accelerates tubular cell injury, and induces subsequent interstitial fibrosis, thus acting as a nephrotoxin.…”

Section: Nephrotoxicity Of Indoxyl Sulfatementioning

confidence: 99%