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Epithelial DPP4 promotes Ang II-driven renal fibrosis by targeting ACE2 activity in the renin-angiotensin system

Yingying Zhang1, Ruizhi Tan2, Lehao Wu1

  • 1Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.

International Journal of Biological Sciences
|July 3, 2025
PubMed

Insights

Dipeptidyl peptidase-IV (DPP4) inhibition ameliorates kidney fibrosis by restoring the renin-angiotensin system (RAS) anti-fibrotic pathway. Targeting epithelial DPP4 offers a novel therapeutic strategy for chronic kidney disease (CKD) progression.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Pharmacology

Background:

  • Renal fibrosis drives chronic kidney disease (CKD) progression to end-stage renal disease (ESRD).
  • The renin-angiotensin system (RAS) plays a critical role in kidney pathology.
  • Epithelial dipeptidyl peptidase-IV (DPP4) levels correlate with CKD progression.

Purpose of the Study:

  • Investigate the role of epithelial DPP4 in renal fibrosis.
  • Elucidate the molecular mechanisms by which DPP4 influences RAS.
  • Evaluate DPP4 inhibition as a therapeutic strategy for CKD.

Main Methods:

  • Utilized unilateral ureteral obstruction (UUO) and ischemia/reperfusion (I/R) injury models in vivo.
  • Employed human epithelial kidney HK-2 cells stimulated with Angiotensin II (Ang II) in vitro.
  • Performed kidney-specific deletion of DPP4 and targeted DPP4 with linagliptin.

Main Results:

  • DPP4 was upregulated in injured kidneys and Ang II-stimulated cells.
  • Kidney-specific DPP4 deletion ameliorated UUO and I/R-induced renal fibrosis.
  • DPP4 directly binds ACE2, inhibiting the Ang(1-7)/MasR axis and inducing the AT1R axis.
  • Linagliptin treatment restored the anti-fibrotic RAS pathway and blocked fibrosis in I/R-injured kidneys.

Conclusions:

  • Epithelial DPP4 acts as a novel inhibitor of the Ang(1-7)/MasR axis and inducer of the AT1R axis.
  • Targeting DPP4 with linagliptin effectively blocks renal fibrosis progression.
  • Epithelial DPP4 is a potential therapeutic target for enhancing RAS anti-fibrotic activity in CKD.
Keywords:
Dipeptidyl peptidase-IVRenal fibrosisRenin-angiotensin system

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