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Inhibition of Angiotensin-Converting Enzyme Ameliorates Renal Fibrosis by Mitigating DPP-4 Level and Restoring Antifibrotic MicroRNAs

Authors
  • Srivastava, Swayam Prakash1,
  • Goodwin, Julie E.
  • Kanasaki, Keizo1, 2, 3
  • Koya, Daisuke1, 2
  • 1 (D.K.)
  • 2 Division of Anticipatory Molecular Food Science and Technology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan
  • 3 Shimane University Faculty of M2dicine, Internal Medicine 1, Enya-cho, Izumo, Shimane 693-8501, Japan
Type
Published Article
Journal
Genes
Publisher
MDPI AG
Publication Date
Feb 18, 2020
Volume
11
Issue
2
Identifiers
DOI: 10.3390/genes11020211
PMID: 32085655
PMCID: PMC7074526
Source
PubMed Central
Keywords
License
Green

Abstract

Two class of drugs 1) angiotensin-converting enzyme inhibitors (ACEis) and 2) angiotensin II receptor blockers (ARBs) are well-known conventional drugs that can retard the progression of chronic nephropathies to end-stage renal disease. However, there is a lack of comparative studies on the effects of ACEi versus ARB on renal fibrosis. Here, we observed that ACEi ameliorated renal fibrosis by mitigating DPP-4 and TGFβ signaling, whereas, ARB did not show. Moreover, the combination of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), one of the substrates of ACE, with ACEi slightly enhanced the inhibitory effects of ACEi on DPP-4 and associated-TGFβ signaling. Further, the comprehensive miRome analysis in kidneys of ACEi+AcSDKP (combination) treatment revealed the emergence of miR-29s and miR-let-7s as key antifibrotic players. Treatment of cultured cells with ACEi alone or in combination with AcSDKP prevented the downregulated expression of miR-29s and miR-let-7s induced by TGFβ stimulation. Interestingly, ACEi also restored miR-29 and miR-let-7 family cross-talk in endothelial cells, an effect that is shared by AcSDKP suggesting that AcSDKP may be partially involved in the anti-mesenchymal action of ACEi. The results of the present study promise to advance our understanding of how ACEi regulates antifibrotic microRNAs crosstalk and DPP-4 associated-fibrogenic processes which is a critical event in the development of diabetic kidney disease.

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