Heparanase in Kidney Disease

Vlag, Johan van der; Buijsers, Baranca

doi:10.1007/978-3-030-34521-1_26

Cited by 14 publications

(19 citation statements)

References 116 publications

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“…Selected molecules exerting little or no side effects will then be examined for oral availability and anti-cancer effects in combination with currently available treatments. We will also study the effect of our lead compounds on other pathological indications involving heparanase, such as chronic inflammation (i.e., colitis, pancreatitis) [51,52], tissue fibrosis [53], kidney dysfunction (i.e., AKI, diabetic nephropathy) [54][55][56][57], and diabetes [58]. Of particular relevance are recent studies on the presumed involvement of heparanase and heparan sulfate in the pathogenesis of COVID-19 [59][60][61][62].…”

Section: Discussionmentioning

confidence: 99%

New Heparanase-Inhibiting Triazolo-Thiadiazoles Attenuate Primary Tumor Growth and Metastasis

Barash

Rangappa²,

Mohan

et al. 2021

Cancers

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Compelling evidence ties heparanase, an endoglycosidase that cleaves heparan sulfate side (HS) chains of proteoglycans, with all steps of tumor development, including tumor initiation, angiogenesis, growth, metastasis, and chemoresistance. Moreover, heparanase levels correlate with shorter postoperative survival of cancer patients, encouraging the development of heparanase inhibitors as anti-cancer drugs. Heparanase-inhibiting heparin/heparan sulfate-mimicking compounds and neutralizing antibodies are highly effective in animal models of cancer progression, yet none of the compounds reached the stage of approval for clinical use. The present study focused on newly synthesized triazolo–thiadiazoles, of which compound 4-iodo-2-(3-(p-tolyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)phenol (4-MMI) was identified as a potent inhibitor of heparanase enzymatic activity, cell invasion, experimental metastasis, and tumor growth in mouse models. To the best of our knowledge, this is the first report showing a marked decrease in primary tumor growth in mice treated with small molecules that inhibit heparanase enzymatic activity. This result encourages the optimization of 4-MMI for preclinical and clinical studies primarily in cancer but also other indications (i.e., colitis, pancreatitis, diabetic nephropathy, tissue fibrosis) involving heparanase, including viral infection and COVID-19.

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Section: Discussionmentioning

confidence: 99%

New Heparanase-Inhibiting Triazolo-Thiadiazoles Attenuate Primary Tumor Growth and Metastasis

Barash

Rangappa²,

Mohan

et al. 2021

Cancers

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“…Glomerular glycocalyx is formed by proteoglycans, glycoproteins, glycolipids, and glycosaminoglycans. Increased expression of proteolytic enzymes (MMP9, hyaluronidase, heparanase), which degrade the glycocalyx, was observed in diabetic patients and implicated in the pathogenesis of albuminuria [ 186 , 187 ]. In experimental DN, GECs-derived ET-1 induces podocyte production of heparanase, which in turn promotes heparan sulphate degradation and glycocalyx disruption on the surface of both podocytes and GECs [ 188 ].…”

Section: Mechanisms Of Podocyte Injurymentioning

confidence: 99%

Mechanisms of podocyte injury and implications for diabetic nephropathy

2022

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Albuminuria is the hallmark of both primary and secondary proteinuric glomerulopathies, including focal segmental glomerulosclerosis (FSGS), obesity-related nephropathy, and diabetic nephropathy (DN). Moreover, albuminuria is an important feature of all chronic kidney diseases (CKDs). Podocytes play a key role in maintaining the permselectivity of the glomerular filtration barrier (GFB) and injury of the podocyte, leading to foot process (FP) effacement and podocyte loss, the unifying underlying mechanism of proteinuric glomerulopathies. The metabolic insult of hyperglycemia is of paramount importance in the pathogenesis of DN, while insults leading to podocyte damage are poorly defined in other proteinuric glomerulopathies. However, shared mechanisms of podocyte damage have been identified. Herein, we will review the role of haemodynamic and oxidative stress, inflammation, lipotoxicity, endocannabinoid (EC) hypertone, and both mitochondrial and autophagic dysfunction in the pathogenesis of the podocyte damage, focussing particularly on their role in the pathogenesis of DN. Gaining a better insight into the mechanisms of podocyte injury may provide novel targets for treatment. Moreover, novel strategies for boosting podocyte repair may open the way to podocyte regenerative medicine.

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“…Heparanase is secreted as a proenzyme, which is internalized to reach late endosomes and lysosomes, where it is activated by cathepsin-L. Active enzyme can translocate not only to the cell surface where it degrades HS of the glycocalyx (this pathway is suppressed under normal conditions and induced in disease resulting in cleavage of HS from the glycocalyx of glomerular endothelial cells and podocytes), but it also can be incorporated into the nucleus or the Golgi apparatus to induce chromatin remodeling and remodeling of intracellular HS, respectively [45]. The mode of nuclear action of heparanase may involve cleaved fragments of HS competing with HS, a known inhibitor of histone acetyltransferase, to disinhibit histone acetylation.…”

Section: Glycocalyx In Kidney Diseasementioning

confidence: 99%

“…In addition to cathepsin-L-induced activation, heparanase synthesis is enhanced by endothelin-1, defective nitric oxide production, and deficiency in 1,25-dihydroxy-vitamin D 3. These alternative mechanisms underscore the therapeutic efficacy of endothelin receptor A antagonists, correction of uncoupled state of endothelial nitric oxide synthase, and supplemental active form of vitamin D, as well as angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (reviewed in [45]). A remarkable novel antagonist of heparinase-1, heparinase-2, lacks enzymatic activity while preserving a high-affinity binding to HS, hence shielding it from the action of heparanase-1 [46] (see Fig.…”

Section: Glycocalyx In Kidney Diseasementioning

confidence: 99%

Ways and Means of Cellular Reconditioning for Kidney Regeneration

Ishiko

Goligorsky

2022

Am J Nephrol

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Background: Mitochondrial, lysosomal, and peroxisomal dysfunction; defective autophagy; mitophagy; and pexophagy, as well as the loss of glycocalyx integrity are known contributors to initiation and progression of diverse kidney diseases. Those cellular organelles are tightly interactive in health, and during development of a disease, damage in one may propagate to others. By extension, it follows that restoring an individual defect may culminate in a broader restorative spectrum and improvement of cell and organ functions. Summary: A novel strategy of reconditioning cellular organellar dysfunction, which we define as refurbishment of pathogenically pivotal intra- or extracellular elements, damaged in the course of disease and impeding restoration, is briefly outlined in this overview. Individual therapeutic reconditioning approaches targeting selected organelles are cataloged. We anticipate that the proposed reconditioning strategy in the future may enrich the arsenal of regenerative medicine and nephrology. Key Message: The arsenal of regenerative medicine and nephrology consisting of organ transplantation, use of stem cells, cell-free approaches, cell reprogramming strategies, and organ engineering has been enriched by the reconditioning strategy. The latter is based on the recognition of two facts that (a) impairment of diverse cellular organelles contributes to pathogenesis of kidney disease and (b) individual organelles are functionally interactively coupled, which explains the “domino effect” leading to their dysfunction. Reconditioning takes advantage of these facts and, while initially directed to restore the function of individual cellular organelles, culminates in the propagation of a therapeutic intervention to account for improved cell and organ function. Examples of such interventions are briefly summarized along the presentation of defective cellular organelles contributing to pathogenesis of kidney disease.

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Heparanase in Kidney Disease

Cited by 14 publications

References 116 publications

New Heparanase-Inhibiting Triazolo-Thiadiazoles Attenuate Primary Tumor Growth and Metastasis

New Heparanase-Inhibiting Triazolo-Thiadiazoles Attenuate Primary Tumor Growth and Metastasis

Mechanisms of podocyte injury and implications for diabetic nephropathy

Ways and Means of Cellular Reconditioning for Kidney Regeneration

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