title: Dipeptidyl peptidase-4 inhibition by Saxagliptin prevents inflammation and renal injury by targeting the Nlrp3/ASC inflammasome.
abstract: BACKGROUND
  Glucagon-like peptide-1 (GLP-1) receptor activation delays the progression of diabetic nephropathy (DN) in rodents. The NOD-like receptor 3 (Nlrp3) inflammasome plays an important role in DN. Dipeptidyl peptidase-4 inhibitors (DPP4I) inhibit the degradation of endogenous GLP-1 and various other active substances. We assessed whether DPP4I attenuates diabetes-induced activation of the inflammasome and progression of DN in mice with type 2 diabetes mellitus (T2DM) and type 1 diabetes mellitus (T1DM).
  
  
  METHODS
  BTBR (T2DM), Akita (T1DM) and their matched non-diabetic control (wild-type (WT)) mice received 8-week treatment with Saxagliptin (Saxa) or vehicle.
  
  
  RESULTS
  Kidney weight and kidney/body weight ratio increased in the BTBR and Akita mice compared to their WT mice. Saxa attenuated these changes in the BTBR, but not in the Akita mice and had no effect in the WT mice. Serum blood urea nitrogen and creatinine significantly increased in the BTBR and Akita mice. Saxa attenuated the increase in the BTBR and Akita mice. Saxa improved glycemic control in the BTBR mice, but had no effect on glucose levels in the Akita and WT mice. Serum C reactive protein, tumor necrosis factor α (TNFα), interleukin (IL)-1β, IL-6 and IL-18 were significantly higher in the BTBR and Akita mice than in the WT mice. Saxa attenuated the increase in the BTBR and Akita mice. Kidney and adipose protein levels of apoptosis-associated speck-like protein 1, NLRP3, TNFα and Caspase-1 were higher in the BTBR and Akita mice than in the WT mice. Saxa reduced the levels in both types of diabetic mice.
  
  
  CONCLUSIONS
  Saxa attenuated diabetes-induced activation of the inflammasome and progression of DN. As Saxa did not affect glucose levels in the Akita mice, these effects are independent of glucose lowering.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA; Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yochai
authors.initials: Y
authors.lastname: Birnbaum
authors.affiliation: Section of Endocrinology, Department of Medicine , Baylor College of Medicine , Houston, Texas , USA.
authors.forename: Mandeep
authors.initials: M
authors.lastname: Bajaj
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA; Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
authors.forename: Jinqiao
authors.initials: J
authors.lastname: Qian
authors.affiliation: Department of Biochemistry and Molecular Biology , University of Texas Medical Branch , Galveston, Texas , USA.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Ye
keywords: Dipeptidyl Peptidase IV; Experimental Diabetes; Inflammation and Complications; Nephropathy