Browsing by Subject "Renal physiology"

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    Evolving Concepts in Uromodulin Biology, Physiology, and Its Role in Disease: a Tale of Two Forms
    (American Heart Association, 2022) LaFavers, Kaice A.; Micanovic, Radmila; Sabo, Angela R.; Maghak, Lauren A.; El-Achkar, Tarek M.; Medicine, School of Medicine
    Uromodulin (or Tamm-Horsfall protein) is a glycoprotein uniquely produced in the kidney by tubular cells of the thick ascending limb of the loop of Henle and early distal tubules. This protein exhibits bidirectional secretion in the urine and in the renal interstitium and circulation. The role of this protein in maintaining renal and systemic homeostasis is becoming increasingly appreciated. Furthermore, perturbations of its functions may play a role in various diseases affecting the kidney and distant organs. In this review, we will discuss important advances in understanding its biology, highlighting the recent discoveries of its secretion and differential precursor processing that generates two forms: a) a highly polymerizing form that is apically excreted in the urine and generates filaments, and b) a non-polymerizing form that retains a polymerization inhibitory pro-peptide and is released basolaterally in the kidney interstitium and circulation, but can also be found in the urine. We will also discuss factors regulating its production and release, taking into account its intricate physiology, and propose best practices to report its levels. We also discuss breaking advances in its role in hypertension, acute kidney injury and progression to chronic disease, immunomodulation and regulating renal and systemic oxidative stress. We anticipate that this work will be a great resource for researchers and clinicians. This review will highlight the importance of defining what regulates the two forms of uromodulin, so that modulation of uromodulin levels and function could become a novel tool in our therapeutic armamentarium against kidney disease.
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    Profiling Immune Cells in the Kidney Using Tissue Cytometry and Machine Learning
    (Wolters Kluwer, 2022-03-28) Winfree, Seth; Al Hasan, Mohammad; El-Achkar, Tarek M.; Medicine, School of Medicine
    The immune system governs key functions that maintain renal homeostasis through various effector cells that reside in or infiltrate the kidney. These immune cells play an important role in shaping adaptive or maladaptive responses to local or systemic stress and injury. We increasingly recognize that microenvironments within the kidney are characterized by a unique distribution of immune cells, the function of which depends on this unique spatial localization. Therefore, quantitative profiling of immune cells in intact kidney tissue becomes essential, particularly at a scale and resolution that allow the detection of differences between the various “nephro-ecosystems” in health and disease. In this review, we discuss advancements in tissue cytometry of the kidney, performed through multiplexed confocal imaging and analysis using the Volumetric Tissue Exploration and Analysis (VTEA) software. We highlight how this tool has improved our understanding of the role of the immune system in the kidney and its relevance in the pathobiology of renal disease. We also discuss how the field is increasingly incorporating machine learning to enhance the analytic potential of imaging data and provide unbiased methods to explore and visualize multidimensional data. Such novel analytic methods could be particularly relevant when applied to profiling immune cells. Furthermore, machine-learning approaches applied to cytometry could present venues for nonexhaustive exploration and classification of cells from existing data and improving tissue economy. Therefore, tissue cytometry is transforming what used to be a qualitative assessment of the kidney into a highly quantitative, imaging-based “omics” assessment that complements other advanced molecular interrogation technologies.