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Over the years, hyaluronic acid (HA) has emerged as an important molecule in nephrological and urological studies involving extracellular matrix (ECM) organization, inflammation, tissue regeneration, and viral sensing. During this time, many have noted the perplexing double-edged nature of the molecule, at times promoting pro-fibrotic events and at other times promoting anti-fibrotic events. Different molecular weights of HA can be attributed to these disparities, though most studies have yet to focus on this subtlety. With regard to the kidney, HA is induced in the initial response phase of injury and is subsequently decreased during disease progression of AKI, CKD, and diabetic nephropathy. These and other kidney diseases force patients, particularly pediatric patients, to face dialysis, surgical procedures, and ultimately, transplant. To summarize the current literature for researchers and pediatric nephrologists, this review aims to expound HA and elucidate its paradoxical effects in multiple kidney diseases using studies that emphasize HA molecular weight when available., Author(s): Aditya Kaul [sup.1] , Kavya L. Singampalli [sup.1] [sup.2] [sup.3] , Umang M. Parikh [sup.1] , Ling Yu [sup.1] , Sundeep G. Keswani [sup.1] , Xinyi Wang [sup.1] Author [...]

In this study we investigated the regulatory role of cell-migration-inducing and hyaluronan-binding protein (CEMIP) in the proliferation and migration of vascular smooth muscle cells (VSMCs). The mRNA and protein levels of CEMIP were upregulated in the plasma samples from patients with atherosclerosis, and in VSMCs stimulated with platelet-derived growth factor-BB (PDGF-BB), compared with plasma from healthy subjects and untreated VSMCs. Silencing CEMIP suppressed PDGF-BB-induced cell migration and proliferation in VSMCs, as determined using a Cell Counting Kit-8 assays, 5-ethynyl-2'-deocyuridine (EDU) assays, flow cytometry, wound healing assays, and Transwell assays. Overexpression of CEMIP promoted the proliferation and migration of VSMCs via activation of the Wnt--[beta]-catenin signaling pathway and the upregulation of its target genes, including matrix met alloproteinase-2, matrix met alloproteinase-7, cyclin D1, and c-myc, whereas CEMIP deficiency showed the opposite effects. The knockdown of CEMIP in [ApoE.sup.-/-] mice by intravenous injection of lentiviral vector expressing si-CEMIP protected against high-fat-diet-induced atherosclerosis, as shown by the reduced aortic lesion areas, aortic sinus lesion areas, and the concentration of blood lipids compared with mice normally expressing CEMIP. These results demonstrated that CEMIP regulates the proliferation and migration of VSMCs in atherosclerosis by activating the WNT--[beta]-catenin signaling pathway, which suggests the therapeutic potential of CEMIP for the management of atherosclerosis. Key words: atherosclerosis, cell-migration-inducing and hyaluronan-binding protein (CEMIP), platelet-derived growth factor-BB (PDGF-BB), WNT--[beta]-catenin signaling, vascular smooth muscle cells (VSMCs). L'objectif de cette étude consistait à examiner le rôle régulateur de la protéine CEMIP (cell-migration-inducing and hyaluronan-binding protein) sur la prolifération et la migration des cellules musculaires lisses vasculaires (CMLV). Les niveaux de l'ARNm et de la protéine CEMIP étaient régulés à la hausse dans les échantillons de plasma de patients atteints d'athérosclérose et dans les CMLV stimulées au facteur de croissance dérivé des plaquettes (PDGF-BB) comparativement aux échantillons de sujets sains et aux CMLV non traitées, respectivement. Le silençage de CEMIP supprimait la migration et la prolifération induites par le PDGF-BB des CMLV telles qu'évaluées par le test de comptage de cellules CCK-8, le marquage à la 5-éthynyl-2'-déoxyuridine (EdU), la cytométrie en flux, un test de cicatrisation et un test sur insert Transwell. La surexpression de CEMIP favorisait la prolifération et la migration des CMLV par l'activation de la voie de signalisation Wnt--[beta]-caténine et la régulation à la hausse de ses gènes cibles dont la métalloprotéase matricielle-2, la métalloprotéase matricielle-7, la cycline D1 et c-myc, alors qu'un déficit en CEMIP exerçait l'effet opposé. Le knockdown de CEMIP chez des souris [ApoE.sup.-/-] réalisé par l'injection intraveineuse d'un vecteur lentiviral exprimant un si-CEMIP protégeait les animaux de l'athérosclérose provoquée par une alimentation riche en gras, comme le démontrait la réduction de la région aortique lésée, de la région du sinus aortique lésée et de la concentration des lipides sanguins, comparativement aux souris chez qui l'expression de CEMIP était normale. Ces résultats démontraient que CEMIP régulait la prolifération et la migration des CMLV dans un contexte d'athérosclérose en activant la voie de signalisation Wnt--[beta]-caténine, ce qui fournit la preuve du potentiel thérapeutique de CEMIP dans la gestion de l'athérosclérose. [Traduit par la Rédaction] Mots-clés : athérosclérose, CEMIP (cell migration-inducing and hyaluronan-binding protein), facteur de croissance dérivé des plaquettes-BB (PDGF-BB), signalisation Wnt--[beta]-caténine, cellules musculaires lisses vasculaires (CMLV)., Introduction Atherosclerosis is a progressive inflammatory disease in which lipids and plaques accumulate in large arteries (Libby 2002). It is the dominant cause of vascular disease, with major clinical consequences [...]

BACKGROUND. Hyaluronan (HA), an extracellular matrix glycosaminoglycan, has been implicated in the pathophysiology of COVID-19 infection, pulmonary hypertension, pulmonary fibrosis, and other diseases, but is not targeted by any approved drugs. We asked whether hymecromone (4-methylumbelliferone [4-MU]), an oral drug approved in Europe for biliary spasm treatment that also inhibits HA in vitro and in animal models, could be repurposed as an inhibitor of HA synthesis in humans. METHODS. We conducted an open-label, single-center, dose-response study of hymecromone in healthy adults. Subjects received hymecromone at 1200 (n = 8), 2400 (n = 9), or 3600 (n = 9) mg/d divided into 3 doses daily, administered orally for 4 days. We assessed safety and tolerability of hymecromone and analyzed HA, 4-MU, and 4-methylumbelliferyl glucuronide (4-MUG; the main metabolite of 4-MU) concentrations in sputum and serum. RESULTS. Hymecromone was well tolerated up to doses of 3600 mg/d. Both sputum and serum drug concentrations increased in a dose-dependent manner, indicating that higher doses lead to greater exposures. Across all dose arms combined, we observed a significant decrease in sputum HA from baseline after 4 days of treatment. We also observed a decrease in serum HA. Additionally, higher baseline sputum HA levels were associated with a greater decrease in sputum HA. CONCLUSION. After 4 days of exposure to oral hymecromone, healthy human subjects experienced a significant reduction in sputum HA levels, indicating this oral therapy may have potential in pulmonary diseases where HA is implicated in pathogenesis. TRIAL REGISTRATION. ClinicalTrials.gov NCT02780752. FUNDING. Stanford Medicine Catalyst, Stanford SPARK, Stanford Innovative Medicines Accelerator program, NIH training grants 5T32AI052073-14 and T32HL129970., Introduction Hyaluronan (HA), an extracellular matrix glycosaminoglycan, plays an important role in inflammation (1, 2). Within injured and infected tissues, HA is produced by stromal cells in response to inflammatory [...]

Successful recovery from lung injury requires the repair and regeneration of alveolar epithelial cells to restore the integrity of gas-exchanging regions within the lung and preserve organ function. Improper regeneration of the alveolar epithelium is often associated with severe pulmonary fibrosis, the latter of which involves the recruitment and activation of fibroblasts, as well as matrix accumulation. Type 2 alveolar epithelial cells (AEC2s) are stem cells in the adult lung that contribute to the lung repair process. The mechanisms that regulate AEC2 renewal are incompletely understood. We provide evidence that expression of the innate immune receptor Toll-like receptor 4 (TLR4) and the extracellular matrix glycosaminoglycan hyaluronan (HA) on AEC2s are important for AEC2 renewal, repair of lung injury and limiting the extent of fibrosis. Either deletion of TLR4 or HA synthase 2 in surfactant-protein-C-positive AEC2s leads to impaired renewal capacity, severe fibrosis and mortality. Furthermore, AEC2s from patients with severe pulmonary fibrosis have reduced cell surface HA and impaired renewal capacity, suggesting that HA and TLR4 are key contributors to lung stem cell renewal and that severe pulmonary fibrosis is the result of distal epithelial stem cell failure., Author(s): Jiurong Liang [1, 2]; Yanli Zhang [1, 2]; Ting Xie [1, 2]; Ningshan Liu [1, 2]; Huaiyong Chen [3]; Yan Geng [1, 2]; Adrianne Kurkciyan [1, 2]; Jessica Monterrosa [...]

We recently reported that abundant deposits of the extracellular matrix polysaccharide hyaluronan (HA) are characteristic of autoimmune insulitis in patients with type 1 diabetes (T1D), but the relevance of these deposits to disease was unclear. Here, we have demonstrated that HA is critical for the pathogenesis of autoimmune diabetes. Using the DO11.10xRIPmOVA mouse model of T1D, we determined that HA deposits are temporally and anatomically associated with the development of insulitis. Moreover, treatment with an inhibitor of HA synthesis, 4-methylumbelliferone (4-MU), halted progression to diabetes even after the onset of insulitis. Similar effects were seen in the NOD mouse model, and in these mice, 1 week of treatment was sufficient to prevent subsequent diabetes. 4-MU reduced HA accumulation, constrained effector T cells to nondestructive insulitis, and increased numbers of intraislet [FOXP3.sup.+] Tregs. Consistent with the observed effects of 4-MU treatment, Treg differentiation was inhibited by HA and anti-CD44 antibodies and rescued by 4-MU in an ERK1/2-dependent manner. These data may explain how peripheral immune tolerance is impaired in tissues under autoimmune attack, including islets in T1D. We propose that 4-MU, already an approved drug used to treat biliary spasm, could be repurposed to prevent, and possibly treat, T1D in at-risk individuals., Introduction Autoimmune type 1 diabetes (T1D) is characterized by progressive, immune cell-mediated destruction of pancreatic β cells and the failure of regulatory mechanisms that normally prevent destructive insulitis, including [FOXP3.sup.+] [...]