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

Abstract Background Dipeptidyl 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 ant...

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Main Authors: Ayano Kubo, Teruo Hidaka, Maiko Nakayama, Yu Sasaki, Miyuki Takagi, Hitoshi Suzuki, Yusuke Suzuki
Format: Article
Language:English
Published: BMC 2020-09-01
Series:BMC Nephrology
Subjects:
Online Access:http://link.springer.com/article/10.1186/s12882-020-02060-9
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author Ayano Kubo
Teruo Hidaka
Maiko Nakayama
Yu Sasaki
Miyuki Takagi
Hitoshi Suzuki
Yusuke Suzuki
author_facet Ayano Kubo
Teruo Hidaka
Maiko Nakayama
Yu Sasaki
Miyuki Takagi
Hitoshi Suzuki
Yusuke Suzuki
author_sort Ayano Kubo
collection DOAJ
description Abstract Background Dipeptidyl 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. Methods The 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. Results DPP-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. Conclusions DPP-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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spelling doaj.art-1c7b87f075d9458bb2434535e662435f2022-12-21T18:55:31ZengBMCBMC Nephrology1471-23692020-09-0121111410.1186/s12882-020-02060-9Protective effects of DPP-4 inhibitor on podocyte injury in glomerular diseasesAyano Kubo0Teruo Hidaka1Maiko Nakayama2Yu Sasaki3Miyuki Takagi4Hitoshi Suzuki5Yusuke Suzuki6Department of Nephrology, Juntendo University Faculty of MedicineDepartment of Nephrology, Juntendo University Faculty of MedicineDepartment of Nephrology, Juntendo University Faculty of MedicineDepartment of Nephrology, Juntendo University Faculty of MedicineDepartment of Nephrology, Juntendo University Faculty of MedicineDepartment of Nephrology, Juntendo University Faculty of MedicineDepartment of Nephrology, Juntendo University Faculty of MedicineAbstract Background Dipeptidyl 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. Methods The 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. Results DPP-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. Conclusions DPP-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.http://link.springer.com/article/10.1186/s12882-020-02060-9DPP-4PodocyteGlomerular diseaseSynaptopodinSaxagliptin
spellingShingle Ayano Kubo
Teruo Hidaka
Maiko Nakayama
Yu Sasaki
Miyuki Takagi
Hitoshi Suzuki
Yusuke Suzuki
Protective effects of DPP-4 inhibitor on podocyte injury in glomerular diseases
BMC Nephrology
DPP-4
Podocyte
Glomerular disease
Synaptopodin
Saxagliptin
title Protective effects of DPP-4 inhibitor on podocyte injury in glomerular diseases
title_full Protective effects of DPP-4 inhibitor on podocyte injury in glomerular diseases
title_fullStr Protective effects of DPP-4 inhibitor on podocyte injury in glomerular diseases
title_full_unstemmed Protective effects of DPP-4 inhibitor on podocyte injury in glomerular diseases
title_short Protective effects of DPP-4 inhibitor on podocyte injury in glomerular diseases
title_sort protective effects of dpp 4 inhibitor on podocyte injury in glomerular diseases
topic DPP-4
Podocyte
Glomerular disease
Synaptopodin
Saxagliptin
url http://link.springer.com/article/10.1186/s12882-020-02060-9
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