title: Saxagliptin reduces renal tubulointerstitial inflammation, hypertrophy and fibrosis in diabetes.
abstract: OBJECTIVE
  In addition to lowering blood glucose in patients with type 2 diabetes mellitus, dipeptidyl peptidase 4 (DPP4) inhibitors have been shown to be antifibrotic and anti-inflammatory. We have previously shown that DPP4 inhibition in human kidney proximal tubular cells exposed to high glucose reduced fibrotic and inflammatory markers. Hence, we wanted to demonstrate renoprotection in an in vivo model.
  
  
  METHODS
  We used a type 1 diabetic animal model to explore the renoprotective potential of saxagliptin independent of glucose lowering. We induced diabetes in enos -/- mice using streptozotocin and matched glucose levels using insulin. Diabetic mice were treated with saxagliptin and outcomes compared with untreated diabetic mice.
  
  
  RESULTS
  We provide novel data that saxagliptin limits renal hypertrophy, transforming growth factor beta-related fibrosis and NF-κBp65-mediated macrophage infiltration. Overall, there was a reduction in histological markers of tubulointerstitial fibrosis. There was no reduction in albuminuria or glomerulosclerosis.
  
  
  CONCLUSIONS
  Our findings highlight the potential of DPP4 inhibition as additional therapy in addressing the multiple pathways to achieve renoprotection in diabetic nephropathy.
authors.affiliation: Renal Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, NSW, Australia.
authors.forename: Muralikrishna
authors.initials: M
authors.lastname: Gangadharan Komala
authors.affiliation: Renal Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, NSW, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Gross
authors.affiliation: Renal Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, NSW, Australia.
authors.forename: Amgad
authors.initials: A
authors.lastname: Zaky
authors.affiliation: Renal Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, NSW, Australia.
authors.forename: Carol
authors.initials: C
authors.lastname: Pollock
authors.affiliation: Renal Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, NSW, Australia.
authors.forename: Usha
authors.initials: U
authors.lastname: Panchapakesan
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000419:Albuminuria / Q000201:enzymology / Q000517:prevention & control; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D004151:Dipeptides / Q000494:pharmacology*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D005921:Glomerulonephritis / Q000201:enzymology / Q000517:prevention & control; D006984:Hypertrophy; D007328:Insulin / Q000097:blood; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D009395:Nephritis, Interstitial / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein; D051900:Smad3 Protein / Q000378:metabolism; D013311:Streptozocin; D051996:Transcription Factor RelA / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D005353:Fibronectins; D007328:Insulin; C498144:Rela protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta; D013311:Streptozocin; C502994:saxagliptin; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; D000218:Adamantane
keywords: DPP4 inhibitors; diabetic nephropathy; saxagliptin; tubulointerstitial fibrosis