Osteopontin Synthesis and Localization along the Human Nephron

Verhulst, Anja; Persy, Veerle P.; Rompay, An R. Van; Verstrepen, Walter A.; Helbert, Mark F.; Broe, Marc E. De

doi:10.1681/asn.v1351210

Cited by 27 publications

(1 citation statement)

References 34 publications

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“…[22] Interestingly, implantation biopsies also showed perinuclear osteopontin staining in the slightly damaged proximal tubular cells (in addition to pronounced apical expression in the distal tubular cells), suggesting that osteopontin expression in proximal tubules may be induced with injury. [24] However, the effect of variation in pre-analytic sources, e.g. diabetes or hypertension, on osteopontin expression require further study.…”

Section: Discussionmentioning

confidence: 99%

Spatial proteomics of human diabetic kidney disease, from health to class III

Kondo

McGrady

Nallapothula

et al. 2023

Preprint

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Aims/Hypothesis: Diabetic kidney disease (DKD) remains a significant cause of morbidity and mortality in people with diabetes. Though animal models have taught us much about the molecular mechanisms of DKD, translating these findings to human disease requires greater knowledge of the molecular changes caused by diabetes in human kidneys. Establishing this knowledge base requires building carefully curated, reliable, and complete repositories of human kidney tissue, as well as tissue proteomics platforms capable of simultaneous, spatially resolved examination of multiple proteins. Methods: We used the multiplexed immunofluorescence platform CO-Detection by indexing (CODEX) to image and analyze the expression of 21 proteins in 23 tissue sections from 12 individuals with diabetes and healthy kidneys (DM, 5 individuals), DKD classes IIA, and IIB (2 individuals per class), IIA-B intermediate (2 individuals), and III (one individual). Results: Analysis of the 21-plex immunofluorescence images revealed 18 cellular clusters, corresponding to 10 known kidney compartments and cell types, including proximal tubules, distal nephron, podocytes, glomerular endothelial and peritubular capillaries, blood vessels, including endothelial cells and vascular smooth muscle cells, macrophages, cells of the myeloid lineage, broad CD45+ inflammatory cells and the basement membrane. DKD progression was associated with co-localized increase in collagen IV deposition and infiltration of inflammatory cells, as well as loss of native proteins of each nephron segment at variable rates. Compartment-specific cellular changes corroborated this general theme, with compartment-specific variations. Cell type frequency and cell-to-cell adjacency highlighted (statistically) significant increase in inflammatory cells and their adjacency to tubular and aSMA+ cells in DKD kidneys. Finally, DKD progression was marked by substantial regional variability within single tissue sections, as well as variability across patients within the same DKD class. The sizable intra-personal variability in DKD severity impacts pathologic classifications, and the attendant clinical decisions, which are usually based on small tissue biopsies. Conclusions/Interpretations: High-plex immunofluorescence images revealed changes in protein expression corresponding to differences in cellular phenotypic composition and microenvironment structure with DKD progression. This initial dataset demonstrates the combined power of curated human kidney tissues, multiplexed immunofluorescence and powerful analysis tools in revealing pathophysiology of human DKD.

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Section: Discussionmentioning

confidence: 99%

Spatial proteomics of human diabetic kidney disease, from health to class III

Kondo

McGrady

Nallapothula

et al. 2023

Preprint

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Dying neurons conduct repair processes in the injured brain through osteopontin expression in cooperation with infiltrated blood monocytes

Yang

et al. 2020

Glia

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The brain has an intrinsic capacity to repair injury, but the specific mechanisms are largely unknown. In this study, we found that, despite their incipient death, damaged neurons play a key repair role with the help of monocytes infiltrated from blood. Monocytes phagocytosed damaged and/or dying neurons that expressed osteopontin (OPN), with possible subsequent activation of their inflammasome pathway, resulting in pyroptosis. During this process, monocytes released CD63‐positive exosome‐like vesicles containing OPN. Importantly, following the exosome‐like vesicles, neuron and astrocyte processes elongated toward the injury core. In addition, exosomes prepared from the injured brain contained OPN, and enhanced neurite outgrowth of cultured neurons in an OPN‐dependent manner. Thus, our results introduce the concept that neurons in the injured brain that are destined to die perceive the stressful condition and begin the regeneration processes through induction of OPN, ultimately executing the repair process with the help of monocytes recruited from the circulation.

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