title: DPP4 inhibition attenuates filtration barrier injury and oxidant stress in the zucker obese rat.
abstract: OBJECTIVE
  Obesity-related glomerulopathy is characterized initially by glomerular hyperfiltration with hypertrophy and then development of proteinuria. Putative mechanisms include endothelial dysfunction and filtration barrier injury due to oxidant stress and immune activation. There has been recent interest in targeting dipeptidyl peptidase 4 (DPP4) enzyme due to increasing role in non-enzymatic cellular processes.
  
  
  METHODS
  The Zucker obese (ZO) rat (aged 8 weeks) fed a normal chow or diet containing the DPP4 inhibitor linagliptin for 8 weeks (83 mg/kg rat chow) was utilized.
  
  
  RESULTS
  Compared to lean controls, there were increases in plasma DPP4 activity along with proteinuria in ZO rats. ZO rats further displayed increases in glomerular size and podocyte foot process effacement. These findings occurred in parallel with decreased endothelial stromal-derived factor-1α (SDF-1α), increased oxidant markers, and tyrosine phosphorylation of nephrin and serine phosphorylation of the mammalian target of rapamycin (mTOR). DPP4 inhibition improved proteinuria along with filtration barrier remodeling, circulating and kidney tissue DPP4 activity, increased active glucagon like peptide-1 (GLP-1) as well as SDF-1α, and improved oxidant markers and the podocyte-specific protein nephrin.
  
  
  CONCLUSIONS
  These data support a role for DPP4 in glomerular filtration function and targeting DPP4 with inhibition improves oxidant stress-related glomerulopathy and associated proteinuria.
authors.affiliation: University of Missouri School of Medicine, Columbia, Missouri, USA; Diabetes and Cardiovascular Center, Columbia, Missouri, USA; Department of Internal Medicine, Columbia, Missouri, USA; Division of Nephrology and Hypertension, Columbia, Missouri, USA; Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Nistala
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.forename: Annayya
authors.initials: A
authors.lastname: Aroor
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Alex
authors.initials: A
authors.lastname: Meuth
authors.forename: William
authors.initials: W
authors.lastname: Knight
authors.forename: Tamara
authors.initials: T
authors.lastname: Hancock
authors.forename: Thomas
authors.initials: T
authors.lastname: Klein
authors.forename: Vincent G
authors.initials: VG
authors.lastname: DeMarco
authors.forename: Adam
authors.initials: A
authors.lastname: Whaley-Connell
mesh_terms: D000818:Animals; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D060730:Glomerular Filtration Barrier / Q000187:drug effects* / Q000293:injuries*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007674:Kidney Diseases / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects; D008297:Male; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D052216:Glucagon-Like Peptide 1