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Protective effects of DPP-4 inhibitor on podocyte injury in glomerular diseases

Authors
  • Kubo, Ayano1
  • Hidaka, Teruo1
  • Nakayama, Maiko1
  • Sasaki, Yu1
  • Takagi, Miyuki1
  • Suzuki, Hitoshi1, 2
  • Suzuki, Yusuke1
  • 1 Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan , Bunkyo-ku, Tokyo (Japan)
  • 2 Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu-City, Chiba, 279-0021, Japan , Urayasu-City (Japan)
Type
Published Article
Journal
BMC Nephrology
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Sep 18, 2020
Volume
21
Issue
1
Identifiers
DOI: 10.1186/s12882-020-02060-9
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundDipeptidyl peptidase-4 (DPP-4) is a serine protease that inhibits the degradation of glucagon-like peptide 1. DPP-4 inhibitors are used worldwide to treat type 2 diabetes mellitus and were recently shown to have pleiotropic effects such as anti-oxidant, anti-inflammatory, and anti-fibrotic actions. DPP-4 inhibitors improve albuminuria and renal injury including glomerular damage independent of its hypoglycemic effect. Although DPP-4 is mainly expressed in the kidney, the physiological function of DPP-4 remains unclear.MethodsThe localization of renal DPP-4 activity was determined in human renal biopsy specimens with glycyl-1-prolyl-4-methoxy-2-naphthylamide and the effects of a DPP-4 inhibitor were examined in human cultured podocyte.ResultsDPP-4 activity under normal conditions was observed in some Bowman’s capsular epithelial cells and proximal tubules, but not in the glomerulus. DPP-4 activity was observed in crescent formation in anti-neutrophil myeloperoxidase cytoplasmic antigen antibody nephritis, nodular lesions in diabetic nephropathy, and some podocytes in focal segmental glomerulosclerosis. Notably, the DPP-4 inhibitor saxagliptin suppressed DPP-4 activity in podocytes and the proximal tubules. To assess the effect of DPP-4 inhibitor on podocytes, human cultured podocytes were injured by Adriamycin, which increased DPP-4 activity; this activity was dose-dependently suppressed by saxagliptin. Treatment with saxagliptin maintained the structure of synaptopodin and RhoA. Saxagliptin also improved the detachment of podocytes.ConclusionsDPP-4 activity induces degradation of synaptopodin and reduction of RhoA, resulting in destruction of the podocyte cytoskeleton. Saxagliptin may have pleiotropic effects to prevent podocyte injury.

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