title: Exogenous activated protein C inhibits the progression of diabetic nephropathy.
abstract: BACKGROUND
  Activated protein C (APC) can regulate immune and inflammatory responses and apoptosis. Protein C transgenic mice develop less diabetic nephropathy but whether exogenous administration of APC suppresses established diabetic nephropathy is unknown.
  
  
  OBJECTIVE
  We investigated the therapeutic potential of APC in mice with streptozotocin-induced diabetic nephropathy.
  
  
  METHODS
  Diabetes was induced in unilaterally nephrectomized C57/Bl6 mice using intraperitoneal (i.p.) injection of streptozotocin. Four weeks later, the mice were treated with i.p. exogenous APC every other day for 1 month.
  
  
  RESULTS
  APC-treated mice had a significantly improved blood nitrogen urea-to-creatinine ratio, urine total protein to creatinine ratio and proteinuria, and had significantly less renal fibrosis as measured by the levels of collagen and hydroxyproline. The renal tissue concentration of monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF) and the RNA expression of platelet-derived growth factor (PDGF), transforming growth factor-β1 and connective tissue growth factor (CTGF) were significantly lower in APC-treated mice than in untreated animals. The percentage of apoptotic cells was reduced and the expression of podocin, nephrin and WT-1 in the glomeruli was significantly improved in mice treated with APC compared with untreated mice. The levels of coagulation markers were not affected by APC treatment.
  
  
  CONCLUSIONS
  Exogenous APC improves renal function and mitigates pathological changes in mice with diabetic nephropathy by suppressing the expression of fibrogenic cytokines, growth factors and apoptosis, suggesting its potential usefulness for the therapy of this disease.
authors.affiliation: Department of Diabetes and Metabolism, Mie University Graduate School of Medicine, Tsu City, Mie Prefecture, Japan.
authors.forename: P
authors.initials: P
authors.lastname: Gil-Bernabe
authors.forename: C N
authors.initials: CN
authors.lastname: D'Alessandro-Gabazza
authors.forename: M
authors.initials: M
authors.lastname: Toda
authors.forename: D
authors.initials: D
authors.lastname: Boveda Ruiz
authors.forename: Y
authors.initials: Y
authors.lastname: Miyake
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.forename: Y
authors.initials: Y
authors.lastname: Onishi
authors.forename: J
authors.initials: J
authors.lastname: Morser
authors.forename: E C
authors.initials: EC
authors.lastname: Gabazza
authors.forename: Y
authors.initials: Y
authors.lastname: Takei
authors.forename: Y
authors.initials: Y
authors.lastname: Yano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D004334:Drug Administration Schedule; D005355:Fibrosis; D006801:Humans; D007274:Injections, Intraperitoneal; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009392:Nephrectomy; D009400:Nephrosclerosis / Q000209:etiology / Q000517:prevention & control; D009929:Organ Size / Q000187:drug effects; D011486:Protein C / Q000008:administration & dosage / Q000494:pharmacology*; D013311:Streptozocin; D013997:Time Factors
chemical_list: D015415:Biomarkers; D018925:Chemokines; D036341:Intercellular Signaling Peptides and Proteins; D011486:Protein C; D013311:Streptozocin