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Kidney Week

Abstract: SA-PO968

Role of Proximal Tubule DPP4 in the Development and Progression of Obesity-Related Kidney Disease

Session Information

  • CKD: Pathobiology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Datta, Manoj Kumar, University of Missouri System, Columbia, Missouri, United States
  • Joshi, Trupti, University of Missouri System, Columbia, Missouri, United States
  • Sen, Sidharth, University of Missouri System, Columbia, Missouri, United States
  • Singh, Pallav, University of Missouri System, Columbia, Missouri, United States
  • Restrepo, Ricardo J., University of Missouri System, Columbia, Missouri, United States
  • Ren, Jing, University of Missouri System, Columbia, Missouri, United States
  • Nistala, Ravi, University of Missouri System, Columbia, Missouri, United States
Background

Western diet (WD) rich in refined sugars and fat, is associated with overnutrition and obesity that can lead to obesity related kidney disease (ORKD). We developed a mouse model of ORKD that mimics human ORKD in its pattern of initial glomerular hyperfiltration followed by decline in GFR, histopathological lesions in the form of proximal tubule brush border vacuolization and injury, basement membrane thickening, glomerular accumulation of fat globules and proteinuria. This model manifested increased proximal tubular (PT) expression and activity of Dipeptidyl Peptidase 4 (DPP4) causing activation of inflammatory pathways and fibrosis. The activation of pro-inflammatory cells and cytokines was suppressed by DPP4 inhibitors, global deletion of DPP4 & PT specific deletion of DPP4 which led to improvement in histopathological lesions and GFR. Therefore we hypothesized that PT DPP4 activation contributes to pathophysiological changes in ORKD.

Methods

PTWT and PTKO (Proximal Tubule specific DPP4 KO) mice were fed a WD and control chow (CD) till they were 6, 16 and 18-27 mths old. Unbiased gene expression analysis was performed on kidney tissue using Bulk RNAseq and mass spec.

Results

WD-feeding increased expression of DPP4 at all time-points and in comparison to CD-fed mice. WD-feeding increased gene expression of many pathways including pro-inflammatory cytokines/chemokines, growth pathways such as mTOR, MAPK, PI3K-Akt and NF-Kb and pathways such as Wnt, NAFLD and insulin resistance. Further analysis of differentially expressed genes revealed cell death/apoptosis gene (trib3, fos) expression was increased in the WD-fed WT animals. WD-fed PTKO showed reduction in expression of pro-survival genes and Wnt pathway genes. However, expression of other pro-inflammatory cytokines and growth pathway genes were largely unchanged or increased further suggesting modulation and/or compensatory increase in expression. This was confirmed with proteomic analysis on the same kidney tissue.

Conclusion

WD-feeding is associated with increased expression of DPP4 and genes in the pro-inflammatory, pro-survival and growth pathways. In PTKO mice, DPP4 expression is much reduced and those of select genes is modulated. Taken together,these results suggest that proximal tubular DPP4 activation contributes to pathophysiological changes in ORKD.

Funding

  • NIDDK Support