Browsing by Author "Brosius, Frank C."

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    Molecular mechanisms and therapeutic targets for diabetic kidney disease
    (Elsevier, 2022) Tuttle, Katherine R.; Agarwal, Rajiv; Alpers, Charles E.; Bakris, George L.; Brosius, Frank C.; Kolkhof, Peter; Uribarri, Jaime; Medicine, School of Medicine
    Diabetic kidney disease has a high global disease burden and substantially increases the risk of kidney failure and cardiovascular events. Despite treatment, there is substantial residual risk of disease progression with existing therapies. Therefore, there is an urgent need to better understand the molecular mechanisms driving diabetic kidney disease to help identify new therapies that slow progression and reduce associated risks. Diabetic kidney disease is initiated by diabetes-related disturbances in glucose metabolism, which then trigger other metabolic, hemodynamic, inflammatory, and fibrotic processes that contribute to disease progression. This review summarizes existing evidence on the molecular drivers of diabetic kidney disease onset and progression, focusing on inflammatory and fibrotic mediators—factors that are largely unaddressed as primary treatment targets and for which there is increasing evidence supporting key roles in the pathophysiology of diabetic kidney disease. Results from recent clinical trials highlight promising new drug therapies, as well as a role for dietary strategies, in treating diabetic kidney disease
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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.