Heparanase and Renal Fibrosis

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Eparanasi: un nuovo biomarker di fibrosi e un potenziale target farmacologico per ridurre la progressione del danno renale cronico

Il trattamento poli-farmacologico ha determinato, nel corso degli anni, un significativo rallentamento della progressione della malattia renale cronica verso lo stadio di uremia terminale, ma siamo ancora distanti dallo sviluppo di interventi terapeutici in grado di bloccare questo inesorabile e irreversibile processo. Studi clinico-patologici hanno chiaramente dimostrato che il principale elemento coinvolto nel danno renale è la fibrosi tubulo-interstiziale e che il meccanismo patogenetico alla base di questa condizione ha inizio in larga parte nel compartimento tubulare. In particolare, il processo di transizione epitelio-mesenchimale gioca un ruolo importante nella genesi del danno cronico. Durante questo processo, le cellule epiteliali tubulari subiscono un incremento significativo di markers di superficie di natura mesenchimale e, grazie al rimodellamento del citoscheletro e alla degradazione della membrana basale, sono in grado di migrare nell'interstizio dove svolgono un ruolo chiave nel processo patogenetico. In questo contesto, sembra avere un ruolo chiave l'enzima eparanasi, una endo-β-D-glucuronidasi che taglia le catene dell'eparan-solfato a livello di siti specifici intracatena, e partecipa attivamente alla degradazione e al rimodellamento della matrice extracellulare. La degradazione dei vari costituenti dell'ECM, inclusi i proteoglicani eparan-solfato fa-vorisce il rilascio di fattori trofici quali il FGF-2 che induce l'espressione dei marcatori mesenchimali alfa-SMA, VIM e FN, porta alla degradazione della membrana basale mediante la secrezione di metalloproteinasi della matrice ed aumenta la motilità cellulare. L'epressione dell'eparanasi è regolata da fattori di trascrizione, dalla metilazione del DNA e da varie molecole endogene. L'importanza di questo enzima è stata confermata clinicamente dal riscontro di una sua iperespressione in preparati istologici di biopsie effettuate in soggetti affetti da nefropatie croniche (per esempio, nefropatia diabetica). Pertanto visto l'importante ruolo dell'eparanasi sono in fase di standardizzazione numerose strategie per inibire la sua espressione genica e/o la sua attività enzimatica. Infine, è stato proposto il suo possibile utilizzo come biomarker di progressione del danno tubulo-interstiziale da utilizzare routinariamente in ambito nefrologico

Compaction in soils of the center and north of Santa Fe

Los suelos de la provincia de Santa Fe presentan diversos estados de compactación, que varían segúnel tipo de suelo y el sistema de manejo aplicado. En este capítulo se presentan las causas genéticas yantrópicas de compactación más comunes con ejemplos zonales. Luego se abordan diversos trabajosrealizados para recuperar la calidad física de los suelos en sistemas agrícolas y ganaderos. Por últimose presentan dos trabajos realizados en los suelos más productivos de toda la provincia de Santa Feque describen los cambios ocurridos en diversas propiedades físicas a través de indicadores, a saber:porosidad total, macroporosidad, capacidad de aeración, índice de inestabilidad, índice de compresión,presión de preconsolidación, densidad crítica para el crecimiento de las plantas.Fil: Imhoff, Silvia del Carmen. Universidad Nacional del Litoral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pilatti, M.. Universidad Nacional del Litoral; ArgentinaFil: Carrizo, Maria Eugenia. Universidad Nacional del Litoral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Masola, María Josefina. Universidad Nacional del Litoral. Facultad de Cs.agrarias. Departamento de Ciencias del Ambiente; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Marano, R.. Universidad Nacional del Litoral; ArgentinaFil: Felli, O.. Universidad Nacional del Litoral; Argentin

In Vitro Identification of New Transcriptomic and miRNomic Profiles Associated with Pulmonary Fibrosis Induced by High Doses Everolimus: Looking for New Pathogenetic Markers and Therapeutic Targets.

The administration of Everolimus (EVE), a mTOR inhibitor used in transplantation and cancer, is often associated with adverse effects including pulmonary fibrosis. Although the underlying mechanism is not fully clarified, this condition could be in part caused by epithelial to mesenchymal transition (EMT) of airway cells. To improve our knowledge, primary bronchial epithelial cells (BE63/3) were treated with EVE (5 and 100 nM) for 24 h. EMT markers (\u3b1-SMA, vimentin, fibronectin) were measured by RT-PCR. Transepithelial resistance was measured by Millicell-ERS ohmmeter. mRNA and microRNA profiling were performed by Illumina and Agilent kit, respectively. Only high dose EVE increased EMT markers and reduced the transepithelial resistance of BE63/3. Bioinformatics showed 125 de-regulated genes that, according to enrichment analysis, were implicated in collagen synthesis/metabolism. Connective tissue growth factor (CTGF) was one of the higher up-regulated mRNA. Five nM EVE was ineffective on the pro-fibrotic machinery. Additionally, 3 miRNAs resulted hyper-expressed after 100 nM EVE and able to regulate 31 of the genes selected by the transcriptomic analysis (including CTGF). RT-PCR and western blot for MMP12 and CTGF validated high-throughput results. Our results revealed a complex biological network implicated in EVE-related pulmonary fibrosis and underlined new potential disease biomarkers and therapeutic targets

Interplay between transglutaminases and heparan sulphate in progressive renal scarring

Transglutaminase-2 (TG2) is a new anti-fibrotic target for chronic kidney disease, for its role in altering the extracellular homeostatic balance leading to excessive build-up of matrix in kidney. However, there is no confirmation that TG2 is the only transglutaminase involved, neither there are strategies to control its action specifically over that of the conserved family-members. In this study, we have profiled transglutaminase isozymes in the rat subtotal nephrectomy (SNx) model of progressive renal scarring. All transglutaminases increased post-SNx peaking at loss of renal function but TG2 was the predominant enzyme. Upon SNx, extracellular TG2 deposited in the tubulointerstitium and peri-glomerulus via binding to heparan sulphate (HS) chains of proteoglycans and co-associated with syndecan-4. Extracellular TG2 was sufficient to activate transforming growth factor-β1 in tubular epithelial cells, and this process occurred in a HS-dependent way, in keeping with TG2-affinity for HS. Analysis of heparin binding of the main transglutaminases revealed that although the interaction between TG1 and HS is strong, the conformational heparin binding site of TG2 is not conserved, suggesting that TG2 has a unique interaction with HS within the family. Our data provides a rationale for a novel anti-fibrotic strategy specifically targeting the conformation-dependent TG2-epitope interacting with HS

The multifaceted roles of perlecan in fibrosis

Perlecan, or heparan sulfate proteoglycan 2 (HSPG2), is a ubiquitous heparan sulfate proteoglycan that has major roles in tissue and organ development and wound healing by orchestrating the binding and signaling of mitogens and morphogens to cells in a temporal and dynamic fashion. In this review, its roles in fibrosis are reviewed by drawing upon evidence from tissue and organ systems that undergo fibrosis as a result of an uncontrolled response to either inflammation or traumatic cellular injury leading to an over production of a collagen-rich extracellular matrix. This review focuses on examples of fibrosis that occurs in lung, liver, kidney, skin, kidney, neural tissues and blood vessels and its link to the expression of perlecan in that particular organ system

Heparanase as active player in endothelial glycocalyx remodeling

The surface of all animal cells is coated with a layer of carbohydrates linked in various ways to the outer side of the plasma membrane. These carbohydrates are mainly bound to proteins in the form of glycoproteins and proteoglycans and together with the glycolipids constitute the so-called glycocalyx. In particular, the endothelial glycocalyx that covers the luminal layer of the endothelium is composed of glycosaminoglycans (heparan sulphate -HS and hyaluronic acid -HA), proteoglycans (syndecans and glypicans) and adsorbed plasma proteins. Thanks to its ability to absorb water, this structure contributes to making the surface of the vessels slippery but at the same time acts by modulating the mechano-transduction of the vessels, the vascular permeability and the adhesion of leukocytes in thus regulating several physiological and pathological events. Among the various enzymes involved in the degradation of the glycocalyx, heparanase (HPSE) has been shown to be particularly involved. This enzyme is responsible for the cutting of heparan sulfate (HS) chains at the level of the proteoglycans of the endothelial glycocalyx whose dysfunction appears to have a role in organ fibrosis, sepsis and viral infection. In this mini-review, we describe the mechanisms by which HPSE contributes to glycocalyx remodeling and then examine the role of glycocalyx degradation in the development of pathological conditions and pharmacological strategies to preserve glycocalyx during disease pathogenesis

Heparanase as a target in cancer therapy.

Heparanase is the unique and specific functional endoglycosidase capable of cleaving heparan sulfate (HS) chains. It exerts its enzymatic activity catalyzing the cleavage of the \u3b2 (1,4)-glycosidic bond between glucuronic acid and glucosamine residue. HS cleavage results in remodelling of the extracellular matrix as well as in regulating the release of many HS-linked molecules such as growth factors, cytokines and enzymes involved in inflammation, wound healing and tumour invasion. A pro-metastatic and pro-angiogenic role for this enzyme has been widely demonstrated in many primary human tumours since high levels of heparanase correlate with lymph node and distant metastasis, elevated micro vessel density and reduced survival of cancer patients. Recently, data have been reported that heparanase regulates heparan sulfate proteoglycan syndecan-1 and promotes its shedding from the cell surface. Shed syndecan-1 in turn controls tumour growth, metastasis and neo-angiogenesis mainly by promoting growth-factor signaling in the tumour milieu. Considering that, once inactivated, there are no other molecules capable of performing the same function, it is evident how this enzyme may be an effective and attractive drug target. Several heparanase inhibitors have been developed and some of them have undergone clinical trials showing efficacy against tumours. In this mini-review we will discuss current knowledge of heparanase involvement in cancer as well as its targeted inhibition as a promising therapeutic option in tumour treatment