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Research article
Protective effects of DPP-4 inhibitor on podocyte injury in glomerular diseases
Yusuke Suzuki
Juntendo University Faculty of Medicine
Corresponding Author
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This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at BMC Nephrology.
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.
Keywords
DPP-4, podocyte, glomerular disease, synaptopodin, saxagliptin
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Due to technical limitations Tables 1 and 2 are available as a download in the Supplementary Files.
This is a list of supplementary files associated with this preprint. Click to download.
- KuboAAdditionalFile1.pptx
Additional file 1. DPP-4-active lesions in human several glomerular diseases In addition to Figures 1 and 2, glomerular DPP-4 staining are shown in several kidney diseases. In cases with ANCA-RN, DPP-4 activity was observed in crescent formation (arrow head). In other patients with DN and FSGS, DPP-4 activity was detected in podocytes (arrow). Scale bar: 50μm
- RevisedTable1.xlsx
- RevisedTable2.xlsx
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On 18 Sep, 2020
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Reviewer #1 agreed
On 12 Aug, 2020
Editor assigned
On 11 Aug, 2020
Editor invited
On 10 Aug, 2020
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On 04 Aug, 2020
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Editorial decision: Major revision
On 08 Jul, 2020
Review #2 received
Received 07 Jul, 2020
Reviewer #2 agreed
On 03 Jun, 2020
Review #1 received
Received 15 Apr, 2020
Reviewers invited
Invitations sent on 29 Mar, 2020
Reviewer #1 agreed
On 29 Mar, 2020
Editor assigned
On 02 Mar, 2020
Submission checks complete
On 01 Mar, 2020
Editor invited
On 01 Mar, 2020
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Subject Areas
Urology & Nephrology
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This preprint is under consideration at BMC Nephrology. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Protective effects of DPP-4 inhibitor on podocyte injury in glomerular diseases
Yusuke Suzuki
Juntendo University Faculty of Medicine
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
Version 2
Posted 10 Aug, 2020
Published
On 18 Sep, 2020
No community comments so far
Review #1 received
Received 25 Aug, 2020
Reviewers invited
Invitations sent on 12 Aug, 2020
Reviewer #1 agreed
On 12 Aug, 2020
Editor assigned
On 11 Aug, 2020
Editor invited
On 10 Aug, 2020
Submission checks complete
On 04 Aug, 2020
No comments provided
Editorial decision: Major revision
On 08 Jul, 2020
Review #2 received
Received 07 Jul, 2020
Reviewer #2 agreed
On 03 Jun, 2020
Review #1 received
Received 15 Apr, 2020
Reviewers invited
Invitations sent on 29 Mar, 2020
Reviewer #1 agreed
On 29 Mar, 2020
Editor assigned
On 02 Mar, 2020
Submission checks complete
On 01 Mar, 2020
Editor invited
On 01 Mar, 2020
First submitted
On 27 Feb, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Urology & Nephrology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at BMC Nephrology.
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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Due to technical limitations Tables 1 and 2 are available as a download in the Supplementary Files.