Protective effects of DPP-4 inhibitor on podocyte injury in glomerular diseases
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.
This is a list of supplementary files associated with this preprint. Click to download.
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
Posted 10 Aug, 2020
On 18 Sep, 2020
Received 25 Aug, 2020
Invitations sent on 12 Aug, 2020
On 12 Aug, 2020
On 11 Aug, 2020
On 10 Aug, 2020
On 04 Aug, 2020
On 08 Jul, 2020
Received 07 Jul, 2020
On 03 Jun, 2020
Received 15 Apr, 2020
Invitations sent on 29 Mar, 2020
On 29 Mar, 2020
On 02 Mar, 2020
On 01 Mar, 2020
On 01 Mar, 2020
On 27 Feb, 2020
Protective effects of DPP-4 inhibitor on podocyte injury in glomerular diseases
Posted 10 Aug, 2020
On 18 Sep, 2020
Received 25 Aug, 2020
Invitations sent on 12 Aug, 2020
On 12 Aug, 2020
On 11 Aug, 2020
On 10 Aug, 2020
On 04 Aug, 2020
On 08 Jul, 2020
Received 07 Jul, 2020
On 03 Jun, 2020
Received 15 Apr, 2020
Invitations sent on 29 Mar, 2020
On 29 Mar, 2020
On 02 Mar, 2020
On 01 Mar, 2020
On 01 Mar, 2020
On 27 Feb, 2020
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.