title: Inhibition of inflammation by pentosan polysulfate impedes the development and progression of severe diabetic nephropathy in aging C57B6 mice.
abstract: Inflammation has a key role in diabetic nephropathy (DN) progression. Pentosan polysulfate (PPS) has been shown to decreases interstitial inflammation and glomerulosclerosis in 5/6 nephrectomized rats. Since PPS has an excellent long-term safety profile in interstitial cystitis treatment, and we recently found that old diabetic C57B6 mice develop DN characterized by extensive tubulointerstitial inflammatory lesions that mimics human DN, we examined the effect of PPS on old diabetic mice. We also examined the anti-inflammatory properties of PPS in renal cells in vitro. Diabetes was induced with streptozotocin in 18 months female (early aging) C57B6 mice. Mice were then randomized to receive oral PPS (25 mg/kg/day) or water for 4 months. The effect of PPS on NF-κB activation and on TNFα, high glucose or advanced glycation end products (AGEs) stimulated proinflammatory gene expression in renal cells was examined. We found that PPS treatment preserved renal function, significantly reduced albuminuria, and markedly decreased the severity of renal lesions, including tubulointerstitial inflammation. PPS also reduced upregulation of TNFα and proinflammatory genes in aging diabetic kidneys. Furthermore, PPS suppressed NF-κB, decreased the proinflammatory actions of TNFα, and decreased high glucose and AGEs stimulated MCP-1 production in vitro. Finally, PPS decreased TNFα-induced increase in albumin permeability in podocyte monolayers. In conclusion, PPS treatment largely prevents the development/progression of nephropathy in aging diabetic mice. As this may be mediated by suppression of TNFα, high glucose, and AGE-stimulated NF-κB activation and inflammation in vitro, the in vivo blockade of DN may be due to the anti-inflammatory properties of PPS.
authors.affiliation: Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
authors.forename: Tian-jun
authors.initials: TJ
authors.lastname: Guan
authors.forename: Shirong
authors.initials: S
authors.lastname: Zheng
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Grosjean
authors.forename: Weicheng
authors.initials: W
authors.lastname: Liu
authors.forename: Huabao
authors.initials: H
authors.lastname: Xiong
authors.forename: Ronald
authors.initials: R
authors.lastname: Gordon
authors.forename: Helen
authors.initials: H
authors.lastname: Vlassara
authors.forename: Gary E
authors.initials: GE
authors.lastname: Striker
authors.forename: Feng
authors.initials: F
authors.lastname: Zheng
mesh_terms: D000284:Administration, Oral; D000375:Aging; D000418:Albumins / Q000378:metabolism; D000419:Albuminuria / Q000503:physiopathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000008:administration & dosage; D017127:Glycation End Products, Advanced / Q000494:pharmacology; D066298:In Vitro Techniques; D007249:Inflammation / Q000235:genetics / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010426:Pentosan Sulfuric Polyester / Q000008:administration & dosage*; D010539:Permeability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000418:Albumins; D000893:Anti-Inflammatory Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D017127:Glycation End Products, Advanced; D018836:Inflammation Mediators; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D010426:Pentosan Sulfuric Polyester; D005947:Glucose