The potential roles of galectin-3 in AKI and CKD

Wang, Fengyun; Zhou, Lihua; Eliaz, Amity; Chang, Hu; Qiang, Xinhua; Li, Ké; Chertow, Glenn M.; Eliaz, Isaac; Peng, Zhiyong

doi:10.3389/fphys.2023.1090724

Cited by 6 publications

(3 citation statements)

References 66 publications

(64 reference statements)

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“…Interestingly, SPP1 LAMs showed distinctive expression of genesets related to extracellular matrix (ECM) formation (e.g. epithelial-mesenchymal transition, collagen formation).For example, tissue remodeling-related genes, such as SPP1 (log 2 (FC) 6.79), FN1 (5.09), MMP2 (2.39), MMP9 (2.21), LGALS3 (1.93) 33,34 , were upregulated. Also, genesets related to cholesterol homeostasis and uptake were higher expressed in SPP1 LAMs.…”

Section: Resultsmentioning

confidence: 99%

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Infiltrative classical monocyte-derived andSPP1lipid-associated macrophages mediate inflammation and fibrosis in ANCA-associated glomerulonephritis

Vegting,

Jongejan,

Neele

et al. 2024

Preprint

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BackgroundKidney macrophage infiltration is a histological hallmark of vasculitic lesions and is strongly linked to disease activity in anti-neutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis (AGN). The precise mechanisms by which kidney macrophages influence local inflammation and long-term damage remain largely unknown.MethodsHere, we investigate kidney macrophage diversity using single-cell transcriptome analysis of 25,485 freshly retrieved unfrozen, high-quality kidney CD45+immune cells from five AGN patients, a lupus nephritis and nephrectomy control. Detailed subclustering of myeloid cells was performed to identify disease-specific macrophage subtypes. Next, transcriptome differences between macrophage subsets and disease serotypes were assessed. Findings were validated by immunostainings of an extended cohort of kidney biopsies and flow cytometric analysis of peripheral blood monocytes.ResultsFour main macrophage subsets were identified, including a classical monocyte-derived macrophage (MDM) subset expressing a chemotactic (CXCL2, CXCL3, CXCL8,CCL3) and pro-inflammatory (IL1β, TNF) set of markers and a osteopontin/SPP1+lipid-associated macrophage (SPP1LAMs) subtype exhibiting distinctive upregulation of fibrotic genesets. AGN samples revealed a markedly increased proportion of CD163+macrophages, predominantly composed of classical MDMs, accompanied by resident-likeC1Qmacrophages, andSPP1LAMs. An analogous trend was observed in the expansion of peripheral blood classical monocytes during active disease. The proteinase 3 (PR3)-AGN subtype exhibited heightened classical MDM infiltration and markers of acute inflammation, while interferon signaling and markers of chronicity were reduced compared to myeloperoxidase (MPO)-AGN.ConclusionsOur findings highlight the expression of inflammatory and fibrotic genes by kidney macrophage subsets in AGN. Classical monocyte dysregulation might contribute to inflammation in the pathogenesis of AGN. Targeting these specific monocyte/macrophage subsets may potentially control the inflammatory cascade and attenuate resulting fibrosis in AGN and kidney disease in general.Key points- Classical monocyte-derived macrophages are predominant in ANCA-associated glomerulonephritis and exhibit chemotactic and pro-inflammatory markers- Osteopontin/SPP1+lipid-associated macrophages (SPP1LAMs) show distinctive upregulation of fibrotic genesets- Understanding of the macrophage immune response supports exploration of macrophage-directed therapies for the treatment of autoimmune kidney diseases

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Section: Resultsmentioning

confidence: 99%

“…LGALS3 (1.93) 33,34 , were upregulated. Also, genesets related to cholesterol homeostasis and uptake were higher expressed in SPP1 LAMs.…”

Section: Enrichment Of Proinflammatory Genesets In Classical Mdms And...mentioning

confidence: 99%

Infiltrative classical monocyte-derived andSPP1lipid-associated macrophages mediate inflammation and fibrosis in ANCA-associated glomerulonephritis

Vegting,

Jongejan,

Neele

et al. 2024

Preprint

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“…Galectin-3-binding protein (Gal-3BP), also known as 90k or Mac-2, is a glycoprotein secreted in the body fluids. As a member of the glycoprotein family, Gal-3BP is a typical protein prone to modifications with other amino acids and was initially identified to be involved in cellular transformation in different cancers [ 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 ]. It contains a carbohydrate recognition domain (CRD), which allows molecules and enzymes to oligomerize and form pentamers macromolecules.…”

Section: Resultsmentioning

confidence: 99%

Recent Advances of Proteomics in Management of Acute Kidney Injury

Pejchinovski¹,

Türkkan²,

Pejchinovski

2023

Diagnostics

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Acute Kidney Injury (AKI) is currently recognized as a life-threatening disease, leading to an exponential increase in morbidity and mortality worldwide. At present, AKI is characterized by a significant increase in serum creatinine (SCr) levels, typically followed by a sudden drop in glomerulus filtration rate (GFR). Changes in urine output are usually associated with the renal inability to excrete urea and other nitrogenous waste products, causing extracellular volume and electrolyte imbalances. Several molecular mechanisms were proposed to be affiliated with AKI development and progression, ultimately involving renal epithelium tubular cell-cycle arrest, inflammation, mitochondrial dysfunction, the inability to recover and regenerate proximal tubules, and impaired endothelial function. Diagnosis and prognosis using state-of-the-art clinical markers are often late and provide poor outcomes at disease onset. Inappropriate clinical assessment is a strong disease contributor, actively driving progression towards end stage renal disease (ESRD). Proteins, as the main functional and structural unit of the cell, provide the opportunity to monitor the disease on a molecular level. Changes in the proteomic profiles are pivotal for the expression of molecular pathways and disease pathogenesis. Introduction of highly-sensitive and innovative technology enabled the discovery of novel biomarkers for improved risk stratification, better and more cost-effective medical care for the ill patients and advanced personalized medicine. In line with those strategies, this review provides and discusses the latest findings of proteomic-based biomarkers and their prospective clinical application for AKI management.

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Galectin-3 protects distal convoluted tubules in rhabdomyolysis-induced kidney injury

Kulow,

Labes,

Czopek

et al. 2024

Pflugers Arch - Eur J Physiol

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Advanced glycation endproducts (AGEs) contribute to cellular damage of various pathologies, including kidney diseases. Acute kidney injury (AKI) represents a syndrome seldom characterized by a single, distinct pathophysiological cause. Rhabdomyolysis-induced acute kidney injury (RIAKI) constitutes roughly 15% of AKI cases, yet its underlying pathophysiology remains poorly understood. Using a murine model of RIAKI induced by muscular glycerol injection, we observed elevated levels of AGEs and the AGE receptor galectin-3 (LGALS3) in the kidney. Immunofluorescence localized LGALS3 to distal nephron segments. According to transcriptomic profiling via next-generation sequencing, RIAKI led to profound changes in kidney metabolism, oxidative stress, and inflammation. Cellular stress was evident in both proximal and distal tubules, as shown by kidney injury markers KIM-1 and NGAL. However, only proximal tubules exhibited overt damage and apoptosis, as detected by routine morphology, active Caspase-3, and TUNEL assay, respectively. In vitro, distal convoluted tubule (DCT) cells challenged with AGEs underwent apoptosis, which was markedly enhanced by Lgals3 siRNA treatment. Thus, in RIAKI, the upregulation of LGALS3 may protect the distal nephron from AGE-mediated damage, while proximal tubules lacking LGALS3 stay at risk. Thus, stimulating LGALS3 in the proximal nephron, if achievable, may attenuate RIAKI.

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The potential roles of galectin-3 in AKI and CKD

Cited by 6 publications

References 66 publications

Infiltrative classical monocyte-derived andSPP1lipid-associated macrophages mediate inflammation and fibrosis in ANCA-associated glomerulonephritis

Infiltrative classical monocyte-derived andSPP1lipid-associated macrophages mediate inflammation and fibrosis in ANCA-associated glomerulonephritis

Recent Advances of Proteomics in Management of Acute Kidney Injury

Galectin-3 protects distal convoluted tubules in rhabdomyolysis-induced kidney injury

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