Uremic Toxins Induce Kidney Fibrosis by Activating Intrarenal Renin–Angiotensin–Aldosterone System Associated Epithelial-to-Mesenchymal Transition

Background: Uremic toxins are considered to have a determinant pathological role in the progression of chronic kidney disease. The aim of this study was to define the putative pathological roles of the renal renin–angiotensin–aldosterone system (RAAS) and renal tubular epithelial-to-mesenchymal transition (EMT) in kidney fibrosis induced by (indoxyl sulfate) IS and (p-cresol sulfate) PCS. Methods: Mouse proximal renal tubular cells (PKSV-PRs) treated with IS or PCS were used. Half-nephrectomized B-6 mice were treated with IS or PCS for 4 weeks. In the losartan treatment study, the study animal was administrated with IS+losartan or PCS+losartan for 4 weeks. Results: IS and PCS significantly activated the intrarenal RAAS by increasing renin, angiotensinogen, and angiotensin 1 (AT1) receptor expression, and decreasing AT2 receptor expression in vitro and in vivo. IS and PCS significantly increased transforming growth factor-b1 (TGF-b1) expression and activated the TGF-b pathway by increasing Smad2/Smad2-P, Smad3/Smad3-P, and Smad4 expression. The expression of the EMT-associated transcription factor Snail was increased by IS and PCS treatment. IS and PCS induced the phenotype of EMT-like transition in renal tubules by increasing the expression of fibronectin and a-smooth muscle actin and decreasing the expression of E-cadherin. Losartan significantly attenuated the expression of TGF-b1 and Snail, and decreased kidney fibrosis induced by IS and PCS in vivo

Suppression of Klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase expression and DNA hypermethylation

The expression of the renoprotective antiaging gene Klotho is decreased in uremia. Recent studies suggest that Klotho may be a tumor suppressor, and its expression may be repressed by DNA hypermethylation in cancer cells. Here we investigated the effects and possible mechanisms by which Klotho expression is regulated during uremia in uninephrectomized B-6 mice given the uremic toxins indoxyl sulfate or p-cresyl sulfate. Cultured human renal tubular HK2 cells treated with these toxins were used as an in vitro model. Injections of indoxyl sulfate or p-cresyl sulfate increased their serum concentrations, kidney fibrosis, CpG hypermethylation of the Klotho gene, and decreased Klotho expression in renal tubules of these mice. The expression of DNA methyltransferases 1, 3a, and 3b isoforms in HK2 cells treated with indoxyl sulfate or p-cresyl sulfate was significantly increased. Specific inhibition of DNA methyltransferase isoform 1 by 5-aza-2′-deoxycytidine caused demethylation of the Klotho gene and increased Klotho expression in vitro. Thus, inhibition of Klotho gene expression by uremic toxins correlates with gene hypermethylation, suggesting that epigenetic modification of specific genes by uremic toxins may be an important pathological mechanism of disease

Chronic Kidney Disease Stage Is a Modulator on the Association between High-Sensitivity C-Reactive Protein and Coronary Vasospastic Angina

The prevalence of coronary vasospasm and also the factors associated with coronary vasospasm in CKD is still unclear. In this cross-sectional study of 859 consecutive CKD patients with angina pectoris received coronary catheterization, we evaluated the factors associated with coronary vasospasm. Patients with vasospasm were older and had higher peripheral blood white cell counts, higher peripheral blood monocyte cell counts, higher haemoglobin levels, higher hs-CRP levels, and lower levels of serum creatinine than patients without vasospasm. The results of multivariate logistic regression analysis revealed that peripheral blood monocyte count and hs-CRP level were independently associated with coronary vasospasm in patients with stage 1 CKD. Only peripheral blood monocyte count but not hs-CRP was independently associated with coronary vasospasm in patients with stages 2 and 3 of CKD. In conclusion, peripheral blood monocyte count is independently associated with coronary vasospasm in patients with stage 1–3 CKD, whereas hs-CRP is only independently associated with coronary vasospasm in patients with stage 1 CKD

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

The Effect of Product Familiarity on Price Discount Framing

Consumer knowledge of prices plays an important role in price management since it not only determines how prices are perceived and valued but also influences consumers' purchase decisions. Previous research has demonstrated that our cognitive judgments are indeed influenced by the way decision problems are framed. Thus, the purpose of this study was to investigate whether degrees of perceptual saving of consumers with different product familiarity are influenced by the presentation form of the price discount. Moreover, the findings demonstrate that for the low-price product category conditions, consumers that are less familiar with the product perceived that there was a more significant difference in price reduction when it was presented in percentage terms than presented in dollar terms. However, when people have a higher level of product familiarity, no matter the price discount information is presented in dollar or percentage terms, there is no significant difference in their perceptual saving

Renin–angiotensin–aldosterone system inhibition with losartan significantly inhibited transforming growth factor-β1/Smads pathway and decreased Snail expression in vitro.

<p>A: ELISA analysis showed that losartan (1, 10, and 100 uM) significantly decreased the transforming growth factor-β1 concentration in the culture medium of PKSV cells treated with indoxyl sulfate (IS) (50 mg/L) and <i>p</i>-cresol sulfate (PCS) (50 mg/L). In addition, the Westren blotting results showed that significantly decreased the expression of Smad2-P, Smad3-P and Snail in PKSV cells treated wioth IS and PCS. (*: <i>P</i><0.05; **: <i>P</i><0.01; ***: <i>P</i><0.001).</p

Indoxyl sulfate and <i>p</i>-cresol sulfate induced epithelial-to-mesenchymal-like transition in vivo.

<p>A: Real-time polymearse chain reaction results show that mice treated with indoxyl sulfate (IS) and <i>p</i>-cresol sulfate (PCS) had significantly increased fibronectin and α- smooth muscle actin (SMA) expression in kidney. E-cadherin expression was significantly decreased in mice treated with IS and PCS. B: Results of immunohistological staining show that the staining for fibronectin and α-SMA was significantly increased in mice treated with IS and PCS. The staining for E-cadherin was significantly decreased in mice treated with IS and PCS. (400×) (*: <i>P</i><0.05; **: <i>P</i><0.01; ***: <i>P</i><0.001, <i>vs.</i> control).</p