Browsing by Author "Pennathur, Subramaniam"

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    Mitochondrial Complex II In Intestinal Epithelial Cells Regulates T-cell Mediated Immunopathology
    (Springer Nature, 2021) Fujiwara, Hideaki; Seike, Keisuke; Brooks, Michael D.; Mathew, Anna V.; Kovalenko, Ilya; Pal, Anupama; Lee, Ho-Joon; Peltier, Daniel; Kim, Stephanie; Liu, Chen; Oravecz-Wilson, Katherine; Li, Lu; Sun, Yaping; Byun, Jaeman; Maeda, Yoshinobu; Wicha, Max S.; Saunders, Tom; Rehemtulla, Alnawaz; Lyssiotis, Costas A.; Pennathur, Subramaniam; Reddy, Pavan; Microbiology and Immunology, School of Medicine
    Intestinal epithelial cell (IEC) damage by T cells contributes to graft-versus-host disease (GVHD), inflammatory bowel disease (IBD) and immune checkpoint blockade (ICB) mediated colitis. But little is known about the target cell intrinsic features that influence disease severity. Herein we identified disruption of oxidative phosphorylation and an increase in succinate levels in the IECs from several distinct in vivo models of T cell mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses identified disruption of IEC intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations. The relevance of IEC intrinsic SDHA in mediating disease severity was confirmed by complementary chemical and genetic experimental approaches and validated in human clinical samples. These data identify a critical role for the alteration of the IEC specific mitochondrial complex II component SDHA in the regulation of the severity of T cell mediated intestinal diseases.
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    Multi-Scalar Data Integration Links Glomerular Angiopoietin-Tie Signaling Pathway Activation With Progression of Diabetic Kidney Disease
    (American Diabetes Association, 2022) Liu, Jiahao; Nair, Viji; Zhao, Yi-yang; Chang, Dong-yuan; Limonte, Christine; Bansal, Nisha; Fermin, Damian; Eichinger, Felix; Tanner, Emily C.; Bellovich, Keith A.; Steigerwalt, Susan; Bhat, Zeenat; Hawkins, Jennifer J.; Subramanian, Lalita; Rosas, Sylvia E.; Sedor, John R.; Vasquez, Miguel A.; Waikar, Sushrut S.; Bitzer, Markus; Pennathur, Subramaniam; Brosius, Frank C.; De Boer, Ian; Chen, Min; Kretzler, Matthias; Ju, Wenjun; Kidney Precision Medicine Project; Michigan Translational Core C-PROBE Investigator Group; Medicine, School of Medicine
    Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD). Prognostic biomarkers reflective of underlying molecular mechanisms are critically needed for effective management of DKD. A three-marker panel was derived from a proteomics analysis of plasma samples by an unbiased machine learning approach from participants (N = 58) in the Clinical Phenotyping and Resource Biobank study. In combination with standard clinical parameters, this panel improved prediction of the composite outcome of ESKD or a 40% decline in glomerular filtration rate. The panel was validated in an independent group (N = 68), who also had kidney transcriptomic profiles. One marker, plasma angiopoietin 2 (ANGPT2), was significantly associated with outcomes in cohorts from the Cardiovascular Health Study (N = 3,183) and the Chinese Cohort Study of Chronic Kidney Disease (N = 210). Glomerular transcriptional angiopoietin/Tie (ANG-TIE) pathway scores, derived from the expression of 154 ANG-TIE signaling mediators, correlated positively with plasma ANGPT2 levels and kidney outcomes. Higher receptor expression in glomeruli and higher ANG-TIE pathway scores in endothelial cells corroborated potential functional effects in the kidney from elevated plasma ANGPT2 levels. Our work suggests that ANGPT2 is a promising prognostic endothelial biomarker with likely functional impact on glomerular pathogenesis in DKD.