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Browsing by Author "Lu, Tzong-Shi"
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Item Initiation of Dialysis Is Associated With Impaired Cardiovascular Functional Capacity.(AHA, 2022-07-19) Arroyo, Eliott; Umukoro, Peter E.; Burney, Heather N.; Li, Yang; Li, Xiaochun; Lane, Kathleen A.; Sher, S. Jawad; Lu, Tzong-Shi; Moe, Sharon M.; Moorthi, Ranjani; Coggan, Andrew R.; McGregor, Gordon; Hiemstra, Thomas F.; Zehnder, Daniel; Lim, Kenneth; Kinesiology, School of Health and Human SciencesBackground The transition to dialysis period carries a substantial increased cardiovascular risk in patients with chronic kidney disease. Despite this, alterations in cardiovascular functional capacity during this transition are largely unknown. The present study therefore sought to assess ventilatory exercise response measures in patients within 1 year of initiating dialysis. Methods and Results We conducted a cross-sectional study of 241 patients with chronic kidney disease stage 5 from the CAPER (Cardiopulmonary Exercise Testing in Renal Failure) study and from the intradialytic low-frequency electrical muscle stimulation pilot randomized controlled trial cohorts. Patients underwent cardiopulmonary exercise testing and echocardiography. Of the 241 patients (age, 48.9 [15.0] years; 154 [63.9%] men), 42 were predialytic (mean estimated glomerular filtration rate, 14 mL·min·1.73 m), 54 had a dialysis vintage ≤12 months, and 145 had a dialysis vintage >12 months. Dialysis vintage ≤12 months exhibited a significantly impaired cardiovascular functional capacity, as assessed by oxygen uptake at peak exercise (18.7 [5.8] mL·min·kg) compared with predialysis (22.7 [5.2] mL·min·kg; <0.001). Dialysis vintage ≤12 months also exhibited reduced peak workload, impaired peak heart rate, reduced circulatory power, and increased left ventricular mass index (<0.05 for all) compared with predialysis. After excluding those with prior kidney transplant, dialysis vintage >12 months exhibited a lower oxygen uptake at peak exercise (17.0 [4.9] mL·min·kg) compared with dialysis vintage ≤12 months (18.9 [5.9] mL·min·kg; =0.033). Conclusions Initiating dialysis is associated with a significant impairment in oxygen uptake at peak exercise and overall decrements in ventilatory and hemodynamic exercise responses that predispose patients to functional dependence. The magnitude of these changes is comparable to the differences between low-risk New York Heart Association class I and higher-risk New York Heart Association class II to IV heart failure.Item Integrin α 5 Is Regulated by miR-218-5p in Endothelial Progenitor Cells(Wolters Kluwer, 2022) Liu, Jialing; Li, Yi; Lyu, Lingna; Xiao, Liang; Memon, Aliza A.; Yu, Xin; Halim, Arvin; Patel, Shivani; Osman, Abdikheyre; Yin, Wenqing; Jiang, Jie; Naini, Said; Lim, Kenneth; Zhang, Aifeng; Williams, Jonathan D.; Koester, Ruth; Qi, Kevin Z.; Fucci, Quynh-Anh; Ding, Lai; Chang, Steven; Patel, Ankit; Mori, Yutaro; Chaudhari, Advika; Bao, Aaron; Liu, Jia; Lu, Tzong-Shi; Siedlecki, Andrew; Medicine, School of MedicineKidney endothelial cells are sensitive to hypoxic injury. This cell type expresses integrin α5 (ITGA5), which is essential to the Tie2 signaling cascade. The microRNA miR-218 is known to increase after hypoxia, but the microRNA’s role in regulating ITGA5 protein synthesis is unclear. In this study, the authors found that miR-218-5p specifically binds to ITGA5 mRNA in human kidney-derived endothelial progenitor cells (EPCs). In an animal model of ischemia/reperfusion injury, cells pretreated with an miR-218-5p mimic were delivered efficiently, whereas an animal model containing an miR-218-2 deletion specific to angioblasts resulted in kidney dysgenesis and impaired migration of mouse kidney-derived EPCs. Understanding the regulation of prominent signaling pathways in EPCs may inform optimization of therapeutic techniques for addressing kidney endothelial cell injury.Item Mapping cardiac remodeling in chronic kidney disease(American Association for the Advancement of Science, 2023) Kaesler, Nadine; Cheng, Mingbo; Nagai, James; O’Sullivan, James; Peisker, Fabian; Bindels, Eric M. J.; Babler, Anne; Moellmann, Julia; Droste, Patrick; Franciosa, Giulia; Dugourd, Aurelien; Saez-Rodriguez, Julio; Neuss, Sabine; Lehrke, Michael; Boor, Peter; Goettsch, Claudia; Olsen, Jesper V.; Speer, Thimoteus; Lu, Tzong-Shi; Lim, Kenneth; Floege, Jürgen; Denby, Laura; Costa, Ivan; Kramann, Rafael; Medicine, School of MedicinePatients with advanced chronic kidney disease (CKD) mostly die from sudden cardiac death and recurrent heart failure. The mechanisms of cardiac remodeling are largely unclear. To dissect molecular and cellular mechanisms of cardiac remodeling in CKD in an unbiased fashion, we performed left ventricular single-nuclear RNA sequencing in two mouse models of CKD. Our data showed a hypertrophic response trajectory of cardiomyocytes with stress signaling and metabolic changes driven by soluble uremia-related factors. We mapped fibroblast to myofibroblast differentiation in this process and identified notable changes in the cardiac vasculature, suggesting inflammation and dysfunction. An integrated analysis of cardiac cellular responses to uremic toxins pointed toward endothelin-1 and methylglyoxal being involved in capillary dysfunction and TNFα driving cardiomyocyte hypertrophy in CKD, which was validated in vitro and in vivo. TNFα inhibition in vivo ameliorated the cardiac phenotype in CKD. Thus, interventional approaches directed against uremic toxins, such as TNFα, hold promise to ameliorate cardiac remodeling in CKD.