Abstract P024: Proximal Tubule Specific Dpp4 Deletion Slows Kidney Disease Progression In Western Diet-fed Obese Mice

Abstract

Background: Obesity is a major risk factor for Chronic Kidney Disease progression to End Stage Renal Disease and/or Dialysis. Increased absorption of fats and/or sugars from Western Diet (WD), likely leads to kidney tubular injury in obesity. We observed that global dipeptidyl peptidase 4 (DPP4) deletion as well as use of inhibitors in WD-fed mice results in decreased kidney injury which, in turn was associated with a decrease in proximal tubule DPP4. Therefore, we hypothesized that proximal tubule (PT) DPP4 activation leads to injury and progression of kidney disease. Methods: PT DPP4-KO and WT littermates were fed a WD starting 4-6 wks of age and continued for 2 years. FITC-sinestrin-based GFR and albuminuria were monitored periodically. Tissue histology was performed at select intervals. GeLC-MS was used to separate kidney peptides and Scaffold 4/iPathwayguide used to analyze the Proteomics data. Results: WD-fed WT mice gained 150-200% weight of chow-fed [CD] mice and had a greater decline in GFR than CD-fed animals over 2 years (50% vs. 20%, p<0.05). WD-fed PT-DPP4-KO mice had a lesser decline (~35%) when compared to WT mice. This was true for both male and female mice. Concomitantly, there was an increase in albuminuria in WD-fed WT mice that was mitigated in PT-DPP4-KO mice. PAS/PSR stained sections showed worsening fibrosis, tubular dilatation and glomerulomegaly, tubular vacuolization in WD-fed WT mice that was mitigated in PT-DPP4-KO mice. Oil Red O staining showed increased fat accumulation in glomeruli and tubules of WD-fed WT mice that was mitigated in KO mice. Proteomics analysis followed by immunoblots showed that WD-feeding led to an increase in cell adhesion proteins and ribosomal machinery that was significantly suppressed by KO. In addition, there was a shift towards reduction in gluconeogenesis and improved fatty acid oxidation in KO mice. Conclusion: Obesity without diabetes can lead to chronic decline in GFR in both male and female mice. DPP4 inhibition may slow the decline if started early in the course of developing obesity and/or metabolic syndrome.