Galectin-3 Expression and Secretion Links Macrophages to the Promotion of Renal Fibrosis

Henderson, Neil C.; MacKinnon, Alison C.; Farnworth, Sarah L.; Kipari, Tiina; Haslett, Christopher; Iredale, John P.; Liu, Fu‐Tong; Hughes, Jeremy; Sethi, Tariq

doi:10.2353/ajpath.2008.070726

Cited by 467 publications

(413 citation statements)

References 48 publications

(61 reference statements)

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“…Interestingly, elevation of CCL2 levels was directly associated with the progression of HPS-PF; a similar association has been observed in IPF and animal models of pulmonary fibrosis (36,37).…”

Section: Pulmonary Fibrosis: Pathogenesismentioning

confidence: 57%

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

et al. 2016

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Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive genetic disorder characterized by oculocutaneous albinism and a bleeding diathesis due to platelet dysfunction. More than 50% of cases worldwide are diagnosed on the Caribbean island of Puerto Rico. Genetic testing plays a growing role in diagnosis; however, not all patients with HPS have identified genetic mutations. In Puerto Rico, patients with HPS are often identified shortly after birth by their albinism, although the degree of hypopigmentation is highly variable. Ten subtypes have been described. Patients with HPS-1, HPS-2, and HPS-4 tend to develop pulmonary fibrosis in Puerto Rico; 100% of patients with HPS-1 develop HPS-PF. HPS-PF and idiopathic pulmonary fibrosis are considered similar entities (albeit with distinct causes) because both can show similar histological disease patterns. However, in contrast to idiopathic pulmonary fibrosis, HPS-PF manifests much earlier, often at 30-40 years of age. The progression of HPS-PF is characterized by the development of dyspnea and increasingly debilitating hypoxemia. No therapeutic interventions are currently approved by the U.S. Food and Drug Administration for the treatment of HPS and HPS-PF. However, the approval of two new antifibrotic drugs, pirfenidone and nintedanib, has prompted new interest in identifying drugs capable of reversing or halting the progression of HPS-PF. Thus, lung transplantation remains the only potentially life-prolonging treatment. At present, two clinical trials are recruiting patients with HPS-PF to identify biomarkers for disease progression. Advances in the diagnosis and management of these patients will require the establishment of multidisciplinary centers of excellence staffed by experts in this disease.

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Section: Pulmonary Fibrosis: Pathogenesismentioning

confidence: 57%

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

et al. 2016

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“…[46][47][48][49] For example, specific ablation of macrophages in UUO kidney of diphtheria toxin (DT)-treated CD11b-DT receptor transgenic mice, 47,49 even at early stage resulted in a reduction in renal fibrosis. 49 Moreover Duffield et al 46 demonstrated an important role for macrophages in maintaining the myofibroblast population in renal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

Tan

Zheng

Hsu

et al. 2013

Laboratory Investigation

127

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A pro-fibrotic role of matrix metalloproteinase-9 (MMP-9) in tubular cell epithelial-mesenchymal transition (EMT) is well established in renal fibrosis; however studies from our group and others have demonstrated some previously unrecognized complexity of MMP-9 that has been overlooked in renal fibrosis. Therefore, the aim of this study was to determine the expression pattern, origin and the exact mechanism underlying the contribution of MMP-9 to unilateral ureteral obstruction (UUO), a well-established model of renal fibrosis via MMP-9 inhibition. Renal MMP-9 expression in BALB/c mice with UUO was examined on day 1, 3, 5, 7, 9, 11 and 14. To inhibit MMP-9 activity, MMP-2/9 inhibitor or MMP-9-neutralizing antibody was administered daily for 4 consecutive days from day 0-3, 6-9 or 10-13 and tissues harvested at day 14. In UUO, there was a bi-phasic early-and late-stage upregulation of MMP-9 activity. Interestingly, tubular epithelial cells (TECs) were the predominant source of MMP-9 during early stage, whereas TECs, macrophages and myofibroblasts produced MMP-9 during late-stage UUO. Early-and late-stage inhibition of MMP-9 in UUO mice significantly reduced tubular cell EMT and renal fibrosis. Moreover, MMP-9 inhibition caused a significant reduction in MMP-9-cleaved osteopontin and macrophage infiltration in UUO kidney. Our in vitro study showed MMP-9-cleaved osteopontin enhanced macrophage transwell migration and MMP-9 of both primary TEC and macrophage induced tubular cell EMT. In summary, our result suggests that MMP-9 of both TEC and macrophage origin may directly or indirectly contribute to the pathogenesis of renal fibrosis via osteopontin cleavage, which, in turn further recruit macrophage and induce tubular cell EMT. Our study also highlights the time dependency of its expression and the potential of stage-specific inhibition strategy against renal fibrosis. KEYWORDS: Epithelial-mesenchymal transition; macrophage; matrix metalloproteinase-9; osteopontin; renal fibrosis; tubular epithelial cell Matrix metalloproteinase-9 (MMP-9), also known as gelatinase B, belongs to a large family of zinc-dependent matrixdegrading enzymes called matrix metalloproteinases (MMPs) that have an important role in both physiological and pathological conditions in vivo. 1 MMPs are well known for their anti-fibrotic effect due to their ability to degrade and remodel extracellular matrix (ECM) proteins, however it has been recognized that MMPs can also exert pro-fibrotic effect under various pathological conditions.Myofibroblasts are the effector cells responsible for the production and secretion of ECM in renal fibrosis. It has been reported that myofibroblasts can derive from the activation of renal interstitial fibroblasts, perivascular fibroblasts and pericytes, from bone marrow-derived stem cells and

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“…They exert various functions depending on their phenotype and pathological context which can result in proor anti-fibrotic effects or have no effects at all (23,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). Apart from a number of chemokines driving their influx and activation such as CX3CR1 (28,30,31,41), several molecules also play an important role including galectin-3 (42,43), the receptor for macrophage colony-stimulating factor (44), the Wnt pathway ligand Wnt7b (45) and interleukin 10 (46).…”

Section: The Role Of Immune Cellsmentioning

confidence: 99%

Renal Allograft Fibrosis: Biology and Therapeutic Targets

Floege

2015

American Journal of Transplantation

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Galectin-3 Expression and Secretion Links Macrophages to the Promotion of Renal Fibrosis

Cited by 467 publications

References 48 publications

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

Renal Allograft Fibrosis: Biology and Therapeutic Targets

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