Efficacy of pentosan polysulfate in in vitro models of lysosomal storage disorders: Fabry and Gaucher Disease.

Gaucher and Fabry diseases are the most prevalent sphingolipidoses. Chronic inflammation is activated in those disorders, which could play a role in pathogenesis. Significant degrees of amelioration occur in patients upon introduction of specific therapies; however, restoration to complete health status is not always achieved. The idea of an adjunctive therapy that targets inflammation may be a suitable option for patients. PPS is a mixture of semisynthetic sulfated polyanions that have been shown to have anti-inflammatory effects in mucopolysaccharidosis type I and II patients and animal models of type I, IIIA and VI. We hypothesized PPS could be a useful adjunctive therapy to inflammation for Gaucher and Fabry diseases. The objective of this work is to analyze the in vitro effect of PPS on inflammatory cytokines in cellular models of Gaucher and Fabry diseases, and to study its effect in Gaucher disease associated in vitro bone alterations. Cultures of peripheral blood mononuclear cells from Fabry and Gaucher patients were exposed to PPS. The secretion of proinflammatory cytokines was significantly reduced. Peripheral blood cells exposed to PPS from Gaucher patients revealed a reduced tendency to differentiate to osteoclasts. Osteoblasts and osteocytes cell lines were incubated with an inhibitor of glucocerebrosidase, and conditioned media was harvested in order to analyze if those cells secrete factors that induce osteoclastogenesis. Conditioned media from this cell cultures exposed to PPS produced lower numbers of osteoclasts. We could demonstrate PPS is an effective molecule to reduce the production of proinflammatory cytokines in in vitro models of Fabry and Gaucher diseases. Moreover, it was effective at ameliorating bone alterations of in vitro models of Gaucher disease. These results serve as preclinical supportive data to start clinical trials in human patients to analyze the effect of PPS as a potential adjunctive therapy for Fabry and Gaucher diseases.

[Pentosan polysulfate sodium prevents kidney morphological changes and albuminuria in rats with type 1 diabetes]. / El pentosán polisulfato de sodio previene las alteraciones morfológicas renales y la albuminuria en ratas con diabetes tipo 1.

Decreased levels of glycosaminoglycans (GAGs) have been observed in the kidney and other organs, in human and animal models of diabetes. Long-term administration of heparins and other glycosaminoglycans has demonstrated a beneficial effect on morphological and functional kidney abnormalities in diabetic rats. We assessed the effect of pentosan polysulfate sodium (PPS), a semi-synthetic glycosaminoglycan with low anticoagulant activity, on kidney involvement in streptozotocin diabetic rats. Diabetes was induced in male Sprague-Dawley rats by i.v. administration of streptozotocin (STZ). Animals were randomly allocated to three groups: C = control, STZ and STZ + PPS = pretreated with PPS (15 mg/kg, s.c.). After three months of follow-up, blood and 24 h-urine samples were obtained, the animals were sacrificed and the kidney microdissected for morphometric analysis. Urinary albumin excretion was markedly increased in untreated diabetic rats (C = 0.26 ± 0.03 vs STZ = 7.75 ± 1.8 mg/24 h) and PPS treatment partially prevented the albumin rise (3.7 ± 0.7 mg/24 h), without affecting the metabolic control HbA1c (C = 3.6 ± 1.7; STZ = 8.82 ± 0.47; STZ + PPS = 8.63 ± 0.54). Electron microscope observation revealed typical renal lesions described in experimental diabetes (STZ group). PPS administration prevents the tubular basement membrane thickening and the loss of cytoarchitecture induced by experimental diabetes. Our data demonstrate that long-term administration of PPS has a favourable effect on morphological and functional abnormalities in kidneys of diabetic rats and suggests a potential therapeutic use for this compound.

Pentosan polysulfate prevents glomerular hypertension and structural injury despite persisting hypertension in 5/6 nephrectomy rats.

Five/six nephrectomy induces systemic and glomerular hypertension, glomerulosclerosis, proteinuria, and tubulointerstitial fibrosis. Polysulfate pentosan (PPS) decreases mesangial proliferation and extracellular matrix accumulation. The aim of this study was to determine whether PPS prevents glomerular hemodynamic changes and renal damage. Micropuncture studies were performed in three groups of eight male Wistar rats. Two groups included rats with 5/6 nephrectomy-one of which was treated with PPS in drinking water (100 mg/kg body wt) and the second of which received normal drinking water-and the third group consisted of normal rats that served as controls. Five/six nephrectomy produced systemic hypertension, a 50% reduction in GFR, and a 67% increase in single-nephron GFR due to elevated glomerular pressure and single-nephron plasma flow as well as proteinuria. Hypertension persisted in PPS-treated animals. Despite a similar reduction in GFR, PPS prevented the rise in single-nephron GFR, glomerular capillary hydrostatic pressure, and proteinuria. By morphometry, glomerular volume was increased by 46% and mesangial area by 94%. Fractional glomerular capillary area decreased by 24%. PPS prevented these changes. Tubular dilatation, epithelial cell atrophy, and increased interstitial area were largely prevented by PPS, as was the interstitial inflammatory infiltrate. These results suggest that the renal protection conferred by PPS was mediated both by prevention of glomerular hypertension as well as suppression of the inflammatory response. It was postulated that this was partly due to the preservation of a greater fraction of functional nephrons.